Graph pangenome captures missing heritability and empowers tomato breeding.

Missing heritability in genome-wide association studies defines a major problem in genetic analyses of complex biological traits1,2. The solution to this problem is to identify all causal genetic variants and to measure their individual contributions3,4. Here we report a graph pangenome of tomato constructed by precisely cataloguing more than 19 million variants from 838 genomes, including 32 new reference-level genome assemblies. This graph pangenome was used for genome-wide association study analyses and heritability estimation of 20,323 gene-expression and metabolite traits. The average estimated trait heritability is 0.41 compared with 0.33 when using the single linear reference genome. This 24% increase in estimated heritability is largely due to resolving incomplete linkage disequilibrium through the inclusion of additional causal structural variants identified using the graph pangenome. Moreover, by resolving allelic and locus heterogeneity, structural variants improve the power to identify genetic factors underlying agronomically important traits leading to, for example, the identification of two new genes potentially contributing to soluble solid content. The newly identified structural variants will facilitate genetic improvement of tomato through both marker-assisted selection and genomic selection. Our study advances the understanding of the heritability of complex traits and demonstrates the power of the graph pangenome in crop breeding.

Atomic Insight into the Enzymatic Selectivity of Acetyltransferase for Endogenous Polyamines.

The N1-Spermidine/spermine acetyltransferase (SSAT) serves as the rate-limiting enzyme in the polyamine metabolism pathway, specifically catalyzing the acetylation of spermidine, spermine, and other specific polyamines. The source of its enzymatic selectivity remains elusive. Here, we used quantum mechanics and molecular mechanics simulations combined with various technologies to explore the enzymatic mechanism of SSAT for endogenous polyamines from an atomic perspective. The static binding and chemical transformation were considered. The binding affinity was identified to be dependent on protonated state of polyamine. The order of the binding affinity for Spm, Spd, and Put is consistent with the experimental results, which is also verified by the dynamic separation of polyamine and SSAT. Hydrogen bond interactions and salt bridges contribute most, and the common hot residues were identified. In addition, the transfer of acetyl and proton between polyamine and AcCoA was discovered to follow a concert mechanism, and thermodynamic properties are responsible for the catalytic efficiency of SSAT. This work may be helpful for development of polyamine derivatives based on catalysis to regulate polyamine metabolism.

Satisfactory Tensile Strength and Strain of Recyclable Polyurethane with a Trimaleimide Structure for Thermal Self-Healing and Anticorrosive Coatings.

Bismaleimide (BMI) is often used as the cross-linking reagent in Diels-Alder (D-A)-type intrinsic self-healing materials (DISMs) to promote the connectivity of damaged surfaces based on reversible D-A bond formation on the molecular scale. Until now, although DISMs have exhibited great potential in the applications of various sensors, electronic skin, and artificial muscles, it is still difficult to prepare DISMs with satisfactory self-healing abilities and high tensile strengths and strains at the same time, thus largely limiting their applications in self-healing anticorrosive coatings. Herein, symmetrical trimaleimide (TMI) was successfully synthesized, and trimaleimide-structured D-A self-healing polyurethane (TMI-DA-PU) was prepared via the reversible D-A reaction (cycloaddition of furan and maleimide). As a DISM, TMI-DA-PU exhibits apparently higher self-healing efficiency (98.7%), tensile strength (25.4 MPa), and strain (1378%) compared to bismaleimide-structured D-A self-healing polyurethane (BMI-DA-PU) (self-healing efficiency, 90.2%; tensile strength, 19.3 MPa; strain, 1174%). In addition, TMI-DA-PU shows a high recycling efficiency (>95%) after 4 cycles of recycling. A series of characterizations indicate that TMI provides more monoene rings as the self-healing sites, forms denser cross-linked structures compared to BMI, and is, thus, more appropriate to be used for DISM applications. Moreover, the barrier abilities of coatings can be semi-quantitatively expressed by the impedance value at 0.01 Hz (|Z|0.01 Hz). The |Z|0.01 Hz value of the TMI-DA-PU coating is 3.93 × 109 Ω cm2 on day 0, which is significantly higher than that of the BMI-DA-PU coating (6.76 × 108 Ω cm2 on day 0), indicating that the denser rigid cross-linked structure of TMI results in the small porosity in the TMI-DA-PU coating, thus effectively improving the anticorrosion performance. The construction of DISMs with the structure of TMI demonstrates immense potential in self-healing anticorrosive coatings.

Identification and verification of immune-related genes for diagnosing the progression of atherosclerosis and metabolic syndrome.

BACKGROUND: Atherosclerosis and metabolic syndrome are the main causes of cardiovascular events, but their underlying mechanisms are not clear. In this study, we focused on identifying genes associated with diagnostic biomarkers and effective therapeutic targets associated with these two diseases. METHODS: Transcriptional data sets of atherosclerosis and metabolic syndrome were obtained from GEO database. The differentially expressed genes were analyzed by RStudio software, and the function-rich and protein-protein interactions of the common differentially expressed genes were analyzed.Furthermore, the hub gene was screened by Cytoscape software, and the immune infiltration of hub gens was analyzed. Finally, relevant clinical blood samples were collected for qRT-PCR verification of the three most important hub genes. RESULTS: A total of 1242 differential genes (778 up-regulated genes and 464 down-regulated genes) were screened from GSE28829 data set. A total of 1021 differential genes (492 up-regulated genes and 529 down-regulated genes) were screened from the data set GSE98895. Then 23 up-regulated genes and 11 down-regulated genes were screened by venn diagram. Functional enrichment analysis showed that cytokines and immune activation were involved in the occurrence and development of these two diseases. Through the construction of the Protein-Protein Interaction(PPI) network and Cytoscape software analysis, we finally screened 10 hub genes. The immune infiltration analysis was further improved. The results showed that the infiltration scores of 7 kinds of immune cells in GSE28829 were significantly different among groups (Wilcoxon Test < 0.05), while in GSE98895, the infiltration scores of 4 kinds of immune cells were significantly different between groups (Wilcoxon Test < 0.05). Spearman method was used to analyze the correlation between the expression of 10 key genes and 22 kinds of immune cell infiltration scores in two data sets. The results showed that there were 42 pairs of significant correlations between 10 genes and 22 kinds of immune cells in GSE28829 (|Cor| > 0.3 & P < 0.05). There were 41 pairs of significant correlations between 10 genes and 22 kinds of immune cells in GSE98895 (|Cor| > 0.3 & P < 0.05). Finally, our results identified 10 small molecules with the highest absolute enrichment value, and the three most significant key genes (CX3CR1, TLR5, IL32) were further verified in the data expression matrix and clinical blood samples. CONCLUSION: We have established a co-expression network between atherosclerotic progression and metabolic syndrome, and identified key genes between the two diseases. Through the method of bioinformatics, we finally obtained 10 hub genes in As and MS, and selected 3 of the most significant genes (CX3CR1, IL32, TLR5) for blood PCR verification. This may be helpful to provide new research ideas for the diagnosis and treatment of AS complicated with MS.

Prognostic value of metabolic syndrome in patients with heart failure and malnutrition.

BACKGROUND: Malnutrition is severely associated with worst prognosis of patients with heart failure (HF). Malnourished patients with the metabolic syndrome (MS) can result in a double burden of malnutrition. We aimed to investigate the impact of the MS on clinical outcomes in malnourished HF patients. METHODS: We examined 529 HF patients at risk of malnutrition with a mean age of (66 ± 10) years and 78% (415) were male. Nutritional status defined primarily by the prognostic nutritional index (PNI), with PNI < 40 being defined as malnutrition. The follow-up endpoint was cardiovascular death or all-cause death. RESULTS: During the 36-month follow-up, survival rates for cardiovascular and all-cause death were significantly lower in the MS group than in the non-MS group (log-rank P < 0.01). Multivariate Cox proportional hazards regression models showed that MS was independently associated with cardiovascular death (HR:1.759, 95%CI:1.351-2.291, p < 0.001) and all-cause death (HR:1.326, 95%CI:1.041-1.689, p = 0.022) in malnourished patients with HF. MS significantly increased the predictive value of cardiovascular death (AUC:0.669, 95%CI:0.623-0.715, p < 0.001) and all-cause death (AUC:0.636, 95%CI:0.585-0.687, p < 0.001) on the basis of established risk factors. The predictive effect of MS on cardiovascular death was independent of sex, age, functional class and left ventricular ejection fraction. CONCLUSIONS: In malnourished patients with HF, MS is an independent risk factor for cardiovascular and all-cause mortality. MS significantly enhance the predictive value for clinical events in patients.

Dual-Mode Undistorted Visual Fluorescent Sensing Strategy through Manipulating the Coffee-Ring Effect on Microfluidic Paper-Based Chip.

To overcome the insufficient sensitivity due to distortion of the fluorescent images by mobile devices, we first developed a novel dual-mode strategy for undistorted visual fluorescent sensing on µPAD by technically manipulating the coffee-ring effect of the fluid sample. Based on the manipulating coffee-ring effect, we divided the horizontal direction of the resulting fluorescence image into 600 pixels and obtained more accurate quantitative information to avoid image distortion. The bovine serum albumin-stabilized gold nanoclusters-copper ion complex was used as the fluorescent probe, combined with a small imaging box and a smartphone, to achieve a rapid testing of histidine in human urine. The output image was analyzed in dual mode: RGB numerical analysis in pixel units and the direct measurement of the fluorescent strips length (limit of detection (LOD) is 0.021 and 0.5 mM, respectively), and improved antidistortion for visual fluorescent sensing. This strategy can overcome the distortion of a smartphone-visualized fluorescent image and shows great potential for rapid and convenient analysis.

Static Binding and Dynamic Transporting-Based Design of Specific Ring-Chain-Ring Acetylcholinesterase Inhibitor: From Galantamine to Natural Product.

Acetylcholinesterase (AChE) is a key target for the current symptomatic treatment of Alzheimer's disease, and galantamine is a clinical anticholinesterase drug with transiently acting characteristic and good selectivity for AChE. The present theoretical-experimental work improves the drug's residence time without reducing the inhibition effect, thus providing a crucial breakthrough for modifying the inhibitor of AChE with better kinetic behavior. The static binding and dynamic delivery properties acquired from atomic view reveal that the galantamine simply occupies a catalytic anionic site, and its release from AChE needs only ∼8.6 kcal/mol. Both of these may cause the short residence time of galantamine. The hotspots and most favorable transport mechanism are identified, and the hydrogen bond and aromatic stacking interactions are observed to play crucial roles for galantamine binding and release in AChE. The typical peripheral anionic site arisen at the delivery process would provide another key occupation to enhance the anti-release ability for inhibitors. The compound with "specific-ring-chain-ring" framework with detailed beneficial modification scheme is summarized, which may improve the residence time of the inhibitor in AChE. The thermodynamic and dynamic properties of galantamine derivatives are also studied. Based on dictamnine, a natural alkaloid, two novel eligible derivatives are designed, synthesized and evaluated, which verifies our prediction. Multiple computational approaches and experimental combinations probably provide a train of thought from both static and dynamic views to modify or design appropriate inhibitors on the basis of specific binding and transportation features.

Molecular dynamic simulations identifying the mechanism of holoenzyme formation by O-GlcNAc transferase and active p38α.

O-N-Acetylglucosamine transferase (OGT) can catalyze the O-GlcNAc modification of thousands of proteins. The holoenzyme formation of OGT and adaptor protein is the precondition for further recognition and glycosylation of the target protein, while the corresponding mechanism is still open. Here, static and dynamic schemes based on statistics can successfully screen the feasible identifying, approaching, and binding mechanism of OGT and its typical adaptor protein p38α. The most favorable interface, energy contribution of hotspots, and conformational changes of fragments were discovered. The hydrogen bond interactions were verified as the main driving force for the whole process. The distinct characteristic of active and inactive p38α is explored and demonstrates that the phosphorylated tyrosine and threonine will form strong ion-pair interactions with Lys714, playing a key role in the dynamic identification stage. Multiple method combinations from different points of view may be helpful for exploring other systems of the protein-protein interactions.

Lithium Atom Surface Diffusion and Delocalized Deposition Propelled by Atomic Metal Catalyst toward Ultrahigh-Capacity Dendrite-Free Lithium Anode.

Lithium metal anode possesses overwhelming capacity and low potential but suffers from dendrite growth and pulverization, causing short lifespan and low utilization. Here, a fundamental novel insight of using single-atomic catalyst (SAC) activators to boost lithium atom diffusion is proposed to realize delocalized deposition. By combining electronic microscopies, time-of-flight secondary ion mass spectrometry, theoretical simulations, and electrochemical analyses, we have unambiguously depicted that the SACs serve as kinetic activators in propelling the surface spreading and lateral redistribution of the lithium atoms for achieving dendrite-free plating morphology. Under the impressive capacity of 20 mA h cm-2, the Li modified with SAC-activator exhibits a low overpotential of ∼50 mV at 5 mA cm-2, a long lifespan of 900 h, and high Coulombic efficiencies during 150 cycles, much better than most literature reports. The so-coupled lithium-sulfur full battery delivers high cycling and rate performances, showing great promise toward the next-generation lithium metal batteries.

The PalWRKY77 transcription factor negatively regulates salt tolerance and abscisic acid signaling in Populus.

High salinity, one of the most widespread abiotic stresses, inhibits photosynthesis, reduces vegetation growth, blocks respiration and disrupts metabolism in plants. In order to survive their long-term lifecycle, trees, such as Populus species, recruit the abscisic acid (ABA) signaling pathway to adapt to a saline environment. However, the molecular mechanism behind the ABA-mediated salt stress response in woody plants remains elusive. We have isolated a WRKY transcription factor gene, PalWRKY77, from Populus alba var. pyramidalis (poplar), the expression of which is repressed by salt stress. PalWRKY77 decreases salt tolerance in poplar. Furthermore, PalWRKY77 negatively regulated ABA-responsive genes and relieved ABA-mediated growth inhibition, indicating that PalWRKY77 is a repressor of the ABA response. In vivo and in vitro assays revealed that PalWRKY77 targets the ABA- and salt-induced PalNAC002 and PalRD26 genes by binding to the W-boxes in their promoters. In addition, overexpression of both PalNAC002 and PalRD26 could elevate salt tolerance in transgenic poplars. These findings reveal a novel negative regulation mechanism for the ABA signaling pathway mediated by PalWRKY77 that results in more sensitivity to salt stress in poplar. This deepens our understanding of the complex responses of woody species to salt stress.

A General Model to Explain Repeated Turnovers of Sex Determination in the Salicaceae.

Dioecy, the presence of separate sexes on distinct individuals, has evolved repeatedly in multiple plant lineages. However, the specific mechanisms by which sex systems evolve and their commonalities among plant species remain poorly understood. With both XY and ZW sex systems, the family Salicaceae provides a system to uncover the evolutionary forces driving sex chromosome turnovers. In this study, we performed a genome-wide association study to characterize sex determination in two Populus species, P. euphratica and P. alba. Our results reveal an XY system of sex determination on chromosome 14 of P. euphratica, and a ZW system on chromosome 19 of P. alba. We further assembled the corresponding sex-determination regions, and found that their sex chromosome turnovers may be driven by the repeated translocations of a Helitron-like transposon. During the translocation, this factor may have captured partial or intact sequences that are orthologous to a type-A cytokinin response regulator gene. Based on results from this and other recently published studies, we hypothesize that this gene may act as a master regulator of sex determination for the entire family. We propose a general model to explain how the XY and ZW sex systems in this family can be determined by the same RR gene. Our study provides new insights into the diversification of incipient sex chromosomes in flowering plants by showing how transposition and rearrangement of a single gene can control sex in both XY and ZW systems.

Highly Sensitive and Reliable Internal-Standard Surface-Enhanced Raman Scattering Microneedles for Determination of Bacterial Metabolites as Infection Biomarkers in Skin Interstitial Fluid.

Microneedles (MNs) are currently one of the most promising tools for skin interstitial fluid (ISF)-based biosensing, while it is still a challenge to expand the detectable biomarkers in ISF due to limited MNs types and detection techniques. Herein, highly sensitive internal-standard surface-enhanced Raman scattering microneedles (IS-SERS-MNs) were developed, which enabled the reliable detection of bacterial metabolites in ISF as new detectable biomarkers for infection diagnosis. The developed IS-SERS-MNs can not only directly detect pyocyanin (a representative bacterial metabolite) present in mouse dermal ISF but also indirectly detect pyocyanin in the hypodermis via its diffusion into the dermis, revealing a new possible pathway for the source of biomarkers in dermal ISF. Moreover, the SERS signal of pyocyanin was also clearly detected at real mouse wounds, indicating that the developed IS-SERS-MNs have great potential in minimally invasive and painless diagnosis of bacterial infection via a new ISF route. This work not only develops IS-SERS-MNs as a powerful tool for expanding the application of SERS-based MNs but also provides a new chance for ISF-related infection diagnosis.

An ion imprinting technology-assisted rotational microfluidic hybrid chip for the fluorescence detection of hexavalent chromium ions.

Ion imprinting technology was integrated on a rotational microfluidic paper- and cloth-based hybrid chip for the sensitive and selective detection of hexavalent chromium (Cr(VI)) ions. The rotational microfluidic hybrid chip consisted of CdTe quantum dot based ion imprinting fluorescence sensing cloth and three layers of paper. Users can collect fluorescence signals conveniently via rotating the paper layer to expose the corresponding cloth-based sensing component. One microfluidic hybrid chip can realize the four-set multiplexed detection of Cr(VI) ions, with each set providing three parallel measurements. Furthermore, the quantitative determination of Cr(VI) ions can be achieved via substituting the calculated fluorescence quenching value into the linear calibration curve. The ion imprinting fluorescence sensing microfluidic hybrid chip provides a simple, efficient, and user-friendly device for Cr(VI) ion detection. Moreover, it might be further adapted for other sensing systems and the point-of-care testing of pollutants in combination with portable instruments or smartphones.

Simultaneous Phenol Removal and Resource Recovery from Phenolic Wastewater by Electrocatalytic Hydrogenation.

Efficient pollutants removal and simultaneous resource recovery from wastewater are of great significance for sustainable development. In this study, an electrocatalytic hydrogenation (ECH) approach was developed to selectively and rapidly transform phenol to cyclohexanol, which possesses high economic value and low toxicity and can be easily recovered from the aqueous solution. A three-dimensional Ru/TiO2 electrode with abundant active sites and massive microflow channels was prepared for efficient phenol transformation. A pseudo-first-order rate constant of 0.135 min-1 was observed for ECH of phenol (1 mM), which was 34-fold higher than that of traditional electrochemical oxidation (EO). Both direct electron transfer and indirect reduction by atomic hydrogen (H*) played pivotal roles in the hydrogenation of phenol ring. The ECH technique also showed excellent performance in a wide pH range of 3-11 and with a high concentration of phenol (10 mM). Moreover, the functional groups (e.g., chloro- and methyl-) on phenol showed little influence on the superiority of the ECH system. This work provides a novel and practical solution for remediation of phenolic wastewater as well as recovery of valuable organic compounds.

Combination of multiple methods and views for recognition, transportation, and structure-guided modification of lysine-specific demethylase phenylcyclopropylamine inhibitor.

Lysine-Specific Demethylase 1 (LSD1) is a typical histone-specific demethylase, which plays an important role in protein methylation modification. It is a member of the amine oxidase family (MAO) that specifically removes methyl groups from monomethylated H3K4, dimethylated H3K4 and H3K9 sites associated with tumorigenesis. Phenylcyclopropylamine derivatives are a class of specific LSD1 inhibitors, drawing attention due to their high efficiency. Here, extensive molecular dynamics (MD) simulations are combined with a three-dimensional quantitative structure-activity relationship (3D-QSAR) in order to design a new phenylcyclopropylamine inhibitor from multiple perspectives. In a ligand-oriented point of view, a 3D-QSAR model with comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) can be built based on the 55 phenylcyclopropylamine compounds targeting LSD1 obtained experimentally. The aromatic and piperazine rings are identified as the potential key groups regulating the activity of the compounds. In an interaction-oriented view, the representative compound is defined with the highest inhibitory efficiency. The binding and delivery mechanism and conformational dependence of activity, including channel and dynamic properties, are studied using RAMD and umbrella sampling technologies. The direct hydrogen bond and conjugated interactions are identified as a major driving force in this procedure. The dominant region of the phenylcyclopropylamine influences the free energy and detects the key residues in recognition and delivery. On the basis of both the ligand and interaction, a series of new inhibitor structures were designed, and two of them showed better efficiency. In order to select the inhibitor with a longer residence time, a comparison is conducted between the designed inhibitors and the experimentally obtained inhibitor from the perspective of static binding and dynamic delivery properties. This work creates new guidance for the phenylcyclopropylamine inhibitor design of LDS1 by combining the ligand and receptor, considering both static and dynamic properties. This scheme could be applied in other inhibitor design systems.

Promotion Effect of the X-Zeolite Host on Encapsulated Platinum Clusters for Selective Hydrogenation of Phenylacetylene to Styrene.

The microenvironment surrounding the metal clusters on a carrier produces a tremendous influence on its catalytic performance. In this work, the promotion effect of the zeolitic inner host on catalytic performance of encapsulated platinum nanoclusters is reported. In the reaction of phenylacetylene semihydrogenation to styrene, Pt@X-zeolite, where platinum nanoclusters are encapsulated into the inner microporosity of the X-zeolite, exhibits an ∼3.37 times increased turnover frequency and a much better selectivity of 87.6% in comparison to the referenced Pt/X-zeolite of 79.3% selectivity to styrene at the same reaction conditions, in which the platinum nanoclusters are located at the exterior of the zeolite. Meanwhile, the Pt@X-zeolite displays a higher stability after 10 cycles of the reaction. Through the detailed characteristics, the excellent performance of Pt@X-zeolite is mainly due to the promotion of the zeolitic framework on the encapsulated Pt clusters, resulting in "electron-deficient" Pt clusters, leading to a stronger interaction with the π* molecular orbitals of phenylacetylene and thus enhancing the activation and conversion of phenylacetylene. The zeolite cavity wrapped with encapsulated Pt clusters regulates the adsorption trend of phenylacetylene through the acetylene group on it, promotes the desorption of styrene, and strengthens its selectivity. Meanwhile, Pt@X-zeolite has an excellent stability through the zeolite framework, which protects the Pt species from being lost. This investigation reveals the importance of the zeolitic microenvironment on the catalytic performance of encapsulated metal species and deepens the cognition for this type of catalyst.

Prevalence of psychiatric diagnosis and related psychopathological symptoms among patients with COVID-19 during the second wave of the pandemic.

BACKGROUND: The possibility of psychopathological symptoms and related risk factors among normal persons and patients infected during the outbreak of COVID-19 has been widely investigated. The mental health outcomes of the second wave of the pandemic remain unclear, especially those of patients with an infection. Thus, this study aims to explore the prevalence of and related risk factors associated with psychopathological symptoms among patients infected with COVID-19 during the second wave. METHOD: A cross-sectional survey was conducted in five isolated wards of a designated hospital in Beijing, China, from July 1 to July 15, 2020. The Mini International Neuropsychiatric Interview (MINI) was conducted to assess psychiatric disorders, and a series of scales were used to measure self-reported psychopathological symptoms and psychosomatic factors. Multivariate regression analysis was used to analyze the risk factors associated with psychopathological symptoms. RESULTS: Among 119 participants with infections, the prevalence of generalized anxiety symptoms (51.3%), depressive symptoms (41.2%), and posttraumatic stress symptoms (PTSS)/posttraumatic stress disorder (PTSD) symptoms (33.6%) was observed. Loneliness, hope, coping strategies, and history of mental disorders were the shared risk or protective factors across several psychopathological symptoms. The perceived impact of COVID-19 is the specific risk factor associated with state anxiety symptoms. CONCLUSIONS: The prevalence of symptoms of depression, anxiety, and PTSS/PTSD is high among patients with infections during the second wave of the pandemic in Beijing. Clinical doctors must realize that these patients will probably experience depressive disorder, anxiety disorders, and PTSS/PTSD, as well as some neuropsychiatric syndromes. Specific mental health care is urgently required to help patients manage the virus during the second wave of the pandemic.

Management of non-compressible torso hemorrhage: An update.

With the widespread adoption of advanced tourniquets, the mortality rate of limb wound hemorrhage has decreased significantly, and non-compressible torso hemorrhage has gradually occupied the leading position of potentially preventable death, both in military and civilian circumstances. With the emergence of novel hemostatic devices and materials, strategies for the management of non-compressible torso hemorrhage have changed significantly. This review summarizes the current treatment strategies and types of equipment for non-compressible torso hemorrhage and suggests future research directions, hoping to provide a comprehensive review for the medical personnel and researchers engaging in this field.

Phylogenomics of the genus Populus reveals extensive interspecific gene flow and balancing selection.

Phylogenetic analysis is complicated by interspecific gene flow and the presence of shared ancestral polymorphisms, particularly those maintained by balancing selection. In this study, we aimed to examine the prevalence of these factors during the diversification of Populus, a model tree genus in the Northern Hemisphere. We constructed phylogenetic trees of 29 Populus taxa using 80 individuals based on re-sequenced genomes. Our species tree analyses recovered four main clades in the genus based on consensus nuclear phylogenies, but in conflict with the plastome phylogeny. A few interspecific relationships remained unresolved within the multiple-species clade because of inconsistent gene trees. Our results indicated that gene flow has been widespread within each clade and also occurred among the four clades during their early divergence. We identified 45 candidate genes with ancient polymorphisms maintained by balancing selection. These genes were mainly associated with mating compatibility, growth and stress resistance. Both gene flow and selection-mediated ancient polymorphisms are prevalent in the genus Populus. These are potentially important contributors to adaptive variation. Our results provide a framework for the diversification of model tree genus that will facilitate future comparative studies.

Synthesis, in vitro and in vivo biological evaluation of novel graveolinine derivatives as potential anti-Alzheimer agents.

A novel series of graveolinine derivatives were synthesized and evaluated as potential anti-Alzheimer agents. Compound 5f exhibited the best inhibitory activity for acetylcholinesterase (AChE) and had surprisingly potent inhibitory activity for butyrylcholinesterase (BuChE), with IC50 values of 0.72 µM and 0.16 µM, respectively. The results from Lineweaver-Burk plot and molecular modeling study indicated non-competitive inhibition of AChE by compound 5f. In addition, these derivatives showed potent self-induced ß-amyloid (Aß) aggregation inhibition. Moreover, 5f didn't show obvious toxicity against PC12 and HepG2 cells at 50 µM. Finally, in vivo studies confirmed that 5f significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, these graveolinine derivatives should be thoroughly and systematically studied for the treatment of Alzheimer's disease.