Tartary buckwheat (Fagopyrum tataricum) is an important pseudocereal crop that is strongly adapted to growth in adverse environments. Its gluten-free grain contains complete proteins with a well-balanced composition of essential amino acids and is a rich source of beneficial phytochemicals that provide significant health benefits. Here, we report a high-quality, chromosome-scale Tartary buckwheat genome sequence of 489.3 Mb that is assembled by combining whole-genome shotgun sequencing of both Illumina short reads and single-molecule real-time long reads, sequence tags of a large DNA insert fosmid library, Hi-C sequencing data, and BioNano genome maps. We annotated 33 366 high-confidence protein-coding genes based on expression evidence. Comparisons of the intra-genome with the sugar beet genome revealed an independent whole-genome duplication that occurred in the buckwheat lineage after they diverged from the common ancestor, which was not shared with rosids or asterids. The reference genome facilitated the identification of many new genes predicted to be involved in rutin biosynthesis and regulation, aluminum stress resistance, and in drought and cold stress responses. Our data suggest that Tartary buckwheat's ability to tolerate high levels of abiotic stress is attributed to the expansion of several gene families involved in signal transduction, gene regulation, and membrane transport. The availability of these genomic resources will facilitate the discovery of agronomically and nutritionally important genes and genetic improvement of Tartary buckwheat.

Lemur tyrosine kinase 2 (LMTK2) belongs to both protein kinase and tyrosine kinase families. LMTK2 is less studied and little is known about its function. Here we demonstrate that LMTK2 modulates NF-κB activity and functions to promote colonic tumorigenesis. We found that LMTK2 protein was abundant in colon cancer cells and LMTK2 knockdown (LMTK2-KD) inhibited proliferation of colon cancer cells through inactivating NF-κB. In unstimulated condition, LMTK2 modulated NF-κB through inhibiting phosphorylation of p65 at Ser468. Mechanistically, LMTK2 phosphorylated protein phosphatase 1A (PP1A) to prevent PP1A from dephosphorylating p-GSK3β(Ser9). The p-GSK3β(Ser9) could not phosphorylate p65 at Ser468, which maintained the basal NF-κB activity. LMTK2 also modulated TNFα-activated NF-κB. LMTK2-KD repressed TNFα-induced IKKβ phosphorylation, IκBα degradation and NF-κB activation, implying that LMTK2 modulates TNFα-activated NF-κB via IKK. These results suggest that LMTK2 modulates basal and TNFα-induced NF-κB activities in different mechanisms. Animal studies show that LMTK2-KD suppressed colon cancer cell xenograft growth, decreased PP1A phosphorylation and increased p-p65(Ser468). Our results reveal the role and underlying mechanism of LMTK2 in colonic tumorigenesis and suggest that LMTK2 may serve as a potential target for chemotherapy of colon cancer.

Dyschromatosis universalis hereditaria (DUH) is a rare genodermatosis characterized by mottled hyperpigmented and hypopigmented macules. SASH1 and ABCB6 have been identified as the causative genes for this disorder. We performed whole exome sequencing on a Chinese family with DUH and genotype-phenotype correlation analysis in DUH and lentiginous phenotype patients. A novel heterozygous missense mutation p.Q518P in SASH1 gene was detected in this family. A majority of patients with SASH1 mutations presented as a distinct clinical phenotype clearly different from that in patients with ABCB6 mutations. Our findings further enrich the reservoir of SASH1 mutations in DUH. The clinical phenotypic difference between SASH1 and ABCB6 variants is suggestive of a close phenotype-genotype link in DUH.

Cultivated rice varieties are all diploid, and polyploidization of rice has long been desired because of its advantages in genome buffering, vigorousness, and environmental robustness. However, a workable route remains elusive. Here, we describe a practical strategy, namely de novo domestication of wild allotetraploid rice. By screening allotetraploid wild rice inventory, we identified one genotype of Oryza alta (CCDD), polyploid rice 1 (PPR1), and established two important resources for its de novo domestication: (1) an efficient tissue culture, transformation, and genome editing system and (2) a high-quality genome assembly discriminated into two subgenomes of 12 chromosomes apiece. With these resources, we show that six agronomically important traits could be rapidly improved by editing O. alta homologs of the genes controlling these traits in diploid rice. Our results demonstrate the possibility that de novo domesticated allotetraploid rice can be developed into a new staple cereal to strengthen world food security.

Prostate cancer is highly dependent on androgens and the androgen receptor (AR). Hormonal therapies inhibit gonadal testosterone production, block extragonadal androgen biosynthesis, or directly antagonize AR. Resistance to medical castration occurs as castration-resistant prostate cancer (CRPC) and is driven by reactivation of the androgen-AR axis. 3β-hydroxysteroid dehydrogenase-1 (3βHSD1) serves as the rate-limiting step for potent androgen synthesis from extragonadal precursors, thereby stimulating CRPC. Genetic evidence in men demonstrates the role of 3βHSD1 in driving CRPC. In postmenopausal women, 3βHSD1 is required for synthesis of aromatase substrates and plays an essential role in breast cancer. Therefore, 3βHSD1 lies at a critical junction for the synthesis of androgens and estrogens, and this metabolic flux is regulated through germline-inherited mechanisms. We show that phosphorylation of tyrosine 344 (Y344) occurs and is required for 3βHSD1 cellular activity and generation of Δ4, 3-keto-substrates of 5α-reductase and aromatase, including in patient tissues. BMX directly interacts with 3βHSD1 and is necessary for enzyme phosphorylation and androgen biosynthesis. In vivo blockade of 3βHSD1 Y344 phosphorylation inhibits CRPC. These findings identify what we believe to be new hormonal therapy pharmacologic vulnerabilities for sex-steroid dependent cancers.

Short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3, OMIM: 613091) is an autosomal recessive disorder. SRTD3 presents clinically with a narrow thorax, short ribs, shortened tubular bones, and acetabular roof abnormalities. Clinical signs of SRTD3 vary among individuals. Pathogenic variants of DYNC2H1 (OMIM: 603297) have been reported to cause SRTD3.

The family Filoviridae comprises many notorious viruses, such as Ebola virus (EBOV) and Marburg virus (MARV), that can infect humans and nonhuman primates. Lloviu virus (LLOV), a less well studied filovirus, is considered a potential pathogen for humans. The VP30 C-terminal domain (CTD) of these filoviruses exhibits nucleoprotein (NP) binding and plays an essential role in viral transcription, replication and assembly. In this study, we confirmed the interactions between LLOV VP30 CTD and its NP fragment, and also determined the crystal structure of the chimeric dimeric LLOV NP-VP30 CTD at 2.50 Å resolution. The structure is highly conserved across the family Filoviridae. While in the dimer structure, only one VP30 CTD binds the NP fragment, which indicates that the interaction between LLOV VP30 CTD and NP is not strong. Our work provides a preliminary model to investigate the interactions between LLOV VP30 and NP and suggests a potential target for anti-filovirus drug development.

Traditional Chinese Medicine (TCM) involves a broad range of empirical testing and refinement and plays an important role in the health maintenance for people all over the world. However, due to the complexity of Chinese herbs, a full understanding of TCM's action mechanisms is still unavailable despite plenty of successful applications of TCM in the treatment of various diseases, including especially cardiovascular diseases (CVD), one of the leading causes of death. Thus in the present work, by incorporating the chemical predictors, target predictors and network construction approaches, an integrated system of TCM has been constructed to systematically uncover the underlying action mechanisms of TCM. From three representative Chinese herbs, i.e., Ligusticum chuanxiong Hort., Dalbergia odorifera T. Chen and Corydalis yanhusuo WT Wang which have been widely used in CVD treatment, by combinational use of drug absorption, distribution, metabolism and excretion (ADME) screening and network pharmacology techniques, we have generated 64 bioactive ingredients and identified 54 protein targets closely associated with CVD, of which 29 are common targets (52.7%) of the three herbs. The result provides new information on the efficiency of the Chinese herbs for the treatment of CVD and also explains one of the basic theories of TCM, i.e., "multiple herbal drugs can treat one disease". The predicted potential targets were then mapped to target-disease and target-signal pathway connections, which revealed the relationships of the active ingredients with their potential targets, diseases and signal systems. This means that for the first time, the action mechanism of these three important Chinese herbs for the treatment of CVD is uncovered, by generating and identifying both their active ingredients and novel targets specifically related to CVD, which clarifies some of the common conceptions in TCM, and thus provides clues to modernize such specific herbal medicines.

The continuous upsurge in soil nitrogen (N) enrichment has had strong impacts on the structure and function of ecosystems. Elucidating how plant ectomycorrhizal fungi (EMF) mutualists respond to this additional N will facilitate the rapid development and implementation of more broadly applicable management and remediation strategies. For this study, we investigated the responses of EMF communities to increased N, and how other abiotic environmental factors impacted them. Consequently, we conducted an eight-year N addition experiment in a poplar plantation in coastal eastern China that included five N addition levels: 0 (N0), 50 (N1), 100 (N2), 150 (N3), and 300 (N4) kg N ha-1 yr-1. We observed that excessive N inputs reduced the colonization rate and species richness of EMF, and altered its community structure and functional traits. The total carbon content of the humus layer and available phosphorus in the mineral soil were important drivers of EMF abundance, while the content of ammonium in the humus layer and mineral soil determined the variations in the EMF community structure and mycelium foraging type. Our findings indicated that long-term N addition induced soil nutrient imbalances that resulted in a severe decline in EMF abundance and loss of functional diversity in poplar plantations.

Structural variations (SVs) and gene copy number variations (gCNVs) have contributed to crop evolution, domestication, and improvement. Here, we assembled 31 high-quality genomes of genetically diverse rice accessions. Coupling with two existing assemblies, we developed pan-genome-scale genomic resources including a graph-based genome, providing access to rice genomic variations. Specifically, we discovered 171,072 SVs and 25,549 gCNVs and used an Oryza glaberrima assembly to infer the derived states of SVs in the Oryza sativa population. Our analyses of SV formation mechanisms, impacts on gene expression, and distributions among subpopulations illustrate the utility of these resources for understanding how SVs and gCNVs shaped rice environmental adaptation and domestication. Our graph-based genome enabled genome-wide association study (GWAS)-based identification of phenotype-associated genetic variations undetectable when using only SNPs and a single reference assembly. Our work provides rich population-scale resources paired with easy-to-access tools to facilitate rice breeding as well as plant functional genomics and evolutionary biology research.

In silico prediction of drug-target interactions from heterogeneous biological data can advance our system-level search for drug molecules and therapeutic targets, which efforts have not yet reached full fruition. In this work, we report a systematic approach that efficiently integrates the chemical, genomic, and pharmacological information for drug targeting and discovery on a large scale, based on two powerful methods of Random Forest (RF) and Support Vector Machine (SVM). The performance of the derived models was evaluated and verified with internally five-fold cross-validation and four external independent validations. The optimal models show impressive performance of prediction for drug-target interactions, with a concordance of 82.83%, a sensitivity of 81.33%, and a specificity of 93.62%, respectively. The consistence of the performances of the RF and SVM models demonstrates the reliability and robustness of the obtained models. In addition, the validated models were employed to systematically predict known/unknown drugs and targets involving the enzymes, ion channels, GPCRs, and nuclear receptors, which can be further mapped to functional ontologies such as target-disease associations and target-target interaction networks. This approach is expected to help fill the existing gap between chemical genomics and network pharmacology and thus accelerate the drug discovery processes.

Anesthetic exposure induces learning and memory impairment and the mechanisms remain unknown. Green tea polyphenols(GTP) have been reported to be neuroprotective. The present study was performed to examine the therapeutic potential of GTP on isoflurane-induced cognitive deficits. Six-week-old male C57BL/6J mice were treated with 1.6% isoflurane for 6 hours. Multiple-dose of GTP at 25 mg/kg for 7 consecutive days and single-dose at 75 mg/kg on the 7th day were respectively administered intraperitoneally to model mice before anesthesia. Fear conditioning test and novel objection recognition were conducted to assess cognition of mice. Superoxide dismutase (SOD) was evaluated using assay kits. Protein expression levels of right hippocampus p-CaMKII, p-CREB and BDNF were examined by Western blot. Our results indicated that 6 h isoflurane anesthesia induced cognitive impairment in early 3 days. Meanwhile, the hippocampus SOD declined in step. The expression levels of p-CaMKII, p-CREB and BDNF were also downregulated. GTP 25mg/kg per day significantly attenuated cognitive dysfunction on Day 3 following isoflurane anesthesia. Moreover, GTP 25mg/kg per day effectively mitigated isodlurane-induced declines of SOD, as well as the p-CaMKII, p-CREB and BDNF levels. However, single-dose at 75 mg/kg of GTP had no significant effects. This study indicated that GTP attenuate isoflurane-induced cognition impairment and this positive effects may be related to its antioxidant properties.

E2F transcription factors are considered to be important drivers of tumour growth. E2F7 is an atypical E2F factor, and its role in glioblastoma remains undefined.

Intramuscular fat (IMF) content is an important factor in porcine meat quality. Previously, we showed that miR-34a was less abundant in liver tissue from pigs with higher backfat thickness, compared to pigs with lower backfat thickness. The purpose of this present study was to explore the role of miR-34a in adipogenesis.

Given the imminent threat of influenza pandemics and continuing emergence of new drug-resistant influenza virus strains, novel strategies for preventing and treating influenza disease are urgently needed. Herbal medicine, used for thousands of years in combinational therapies (Herb Formula), plays a significant role in stimulating the host immune system in vivo, and meanwhile, in fighting against the pandemic by directly inhibiting influenza virus in vitro. Such potential Janus functions may spark interest in therapeutic manipulation of virus diseases. Unfortunately, the molecular mechanism of the Janus functions of the medicinal herbs in the treatment of influenza remains unclear. In this work, to illustrate the therapeutic concept of Janus functions in the treatment of influenza, we have introduced a novel systems pharmacology model that integrates pharmacokinetic screening, targeting and network analysis of two representative herbs Lonicera japonica and Fructus Forsythiae that are efficient in the treatment of influenza, inflammation and other diseases. 50 Chemicals with favorable pharmacokinetic profiles have been identified for the two herbs, and the ligand-target network was constructed by complementing the literature-based experimental data deposited in DrugBank. The annotation of these chemicals was assigned using a novel drug targeting approach, and mapped to target-disease and drug-target-pathway networks. The overall data suggest that the medicinal herbs function by indirectly suppressing the virus proliferation via regulating the immune systems in hosts, and also, by directly inhibiting virus proliferation through targeting viral proteins essential for the viral life cycle. For the first time, we have demonstrated the mechanism of medicinal herbs in prevention and treatment of virus diseases via the Janus functions on a systematic level.

Compound Danshen Formula (CDF) is a widely used Traditional Chinese Medicine (TCM) which has been extensively applied in clinical treatment of cardiovascular diseases (CVDs). However, the underlying mechanism of clinical administrating CDF on CVDs is not clear. In this study, the pharmacological effect of CDF on CVDs was analyzed at a systemic point of view. A systems-pharmacological model based on chemical, chemogenomics and pharmacological data is developed via network reconstruction approach. By using this model, we performed a high-throughput in silico screen and obtained a group of compounds from CDF which possess desirable pharmacodynamical and pharmacological characteristics. These compounds and the corresponding protein targets are further used to search against biological databases, such as the compound-target associations, compound-pathway connections and disease-target interactions for reconstructing the biologically meaningful networks for a TCM formula. This study not only made a contribution to a better understanding of the mechanisms of CDF, but also proposed a strategy to develop novel TCM candidates at a network pharmacology level.

Snapdragon (Antirrhinum majus L.), a member of the Plantaginaceae family, is an important model for plant genetics and molecular studies on plant growth and development, transposon biology and self-incompatibility. Here we report a near-complete genome assembly of A. majus cultivar JI7 (A. majus cv.JI7) comprising 510 Megabases (Mb) of genomic sequence and containing 37,714 annotated protein-coding genes. Scaffolds covering 97.12% of the assembled genome were anchored on eight chromosomes. Comparative and evolutionary analyses revealed that a whole-genome duplication event occurred in the Plantaginaceae around 46-49 million years ago (Ma). We also uncovered the genetic architectures associated with complex traits such as flower asymmetry and self-incompatibility, identifying a unique duplication of TCP family genes dated to around 46-49 Ma and reconstructing a near-complete ψS-locus of roughly 2 Mb. The genome sequence obtained in this study not only provides a representative genome sequenced from the Plantaginaceae but also brings the popular plant model system of Antirrhinum into the genomic age.

Alfalfa (Medicago sativa) is one of the most important forage crops in the world; however, its molecular genetics and breeding research are hindered due to the lack of a high-quality reference genome. Here, we report a de novo assembled 816-Mb high-quality, chromosome-level haploid genome sequence for 'Zhongmu No.1' alfalfa, a heterozygous autotetraploid. The contig N50 is 3.92 Mb, and 49 165 genes are annotated in the genome. The alfalfa genome is estimated to have diverged from M. truncatula approximately 8 million years ago. Genomic population analysis of 162 alfalfa accessions revealed high genetic diversity, weak population structure, and extensive gene flow from wild to cultivated alfalfa. Genome-wide association studies identified many candidate genes associated with important agronomic traits. Furthermore, we showed that MsFTa2, a Flowering Locus T homolog, whose expression is upregulated in salt-resistant germplasms, may be associated with fall dormancy and salt resistance. Taken together, these genomic resources will facilitate alfalfa genetic research and agronomic improvement.

Solute carrier family 35 (SLC35) is one of a large number of membrane transporter protein families. Member D3 of this family is thought to be involved in adipose deposition and metabolic control.

BACKGROUNDGenetics of estrogen synthesis and breast cancer risk has been elusive. The 1245A→C missense-encoding polymorphism in HSD3B1, which is common in White populations, is functionally adrenal permissive and increases synthesis of the aromatase substrate androstenedione. We hypothesized that homozygous inheritance of the adrenal-permissive HSD3B1(1245C) is associated with postmenopausal estrogen receptor-positive (ER-positive) breast cancer.METHODSA prospective study of postmenopausal ER-driven breast cancer was done for determination of HSD3B1 and circulating steroids. Validation was performed in 2 other cohorts. Adrenal-permissive genotype frequency was compared between postmenopausal ER-positive breast cancer, the general population, and postmenopausal ER-negative breast cancer.RESULTSProspective and validation studies had 157 and 538 patients, respectively, for the primary analysis of genotype frequency by ER status in White female breast cancer patients who were postmenopausal at diagnosis. The adrenal-permissive genotype frequency in postmenopausal White women with estrogen-driven breast cancer in the prospective cohort was 17.5% (21/120) compared with 5.4% (2/37) for ER-negative breast cancer (P = 0.108) and 9.6% (429/4451) in the general population (P = 0.0077). Adrenal-permissive genotype frequency for estrogen-driven postmenopausal breast cancer was validated using Cambridge and The Cancer Genome Atlas data sets: 14.4% (56/389) compared with 6.0% (9/149) for ER-negative breast cancer (P = 0.007) and the general population (P = 0.005). Circulating androstenedione concentration was higher with the adrenal-permissive genotype (P = 0.03).CONCLUSIONAdrenal-permissive genotype is associated with estrogen-driven postmenopausal breast cancer. These findings link genetic inheritance of endogenous estrogen exposure to estrogen-driven breast cancer.FUNDINGNational Cancer Institute, NIH (R01CA236780, R01CA172382, and P30-CA008748); and Prostate Cancer Foundation Challenge Award.