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Cytochrome bc1 complex (complex Ⅲ) is one of the most important targets for drug and fungicide discovery. Metyltetraprole (MET) is a novel inhibitor of complex Ⅲ, which has activity against the major reported mutations G143A and F129L of quinone site inhibitor (QoI)-resistant isolates. However, the anti-resistance mechanism of MET is still elusive and very intriguing to be explored. Here, we determined the near-atomic resolution structures of isolated complex III (2.88 Å) and MET-bound complex III (3.26 Å) by cryo-electron microscopy (cryo-EM), showing that MET exhibited a different binding mode from azoxystrobin, a typical QoI. MET could bind to the G143A or F129L mutated complex as well as to the wild-type complex III, whereas the binding affinity of azoxystrobin to the G143A or F129L mutants decreased significantly compared to the wild-type. This work provided a structural basis for the design of the next generation of inhibitors to overcome the resistance.

Novel and potent inhibitors targeting succinate-ubiquinone oxidoreductase were discovered from the natural product sclerotiorin for the first time.

Succinate dehydrogenase (SDH, EC 1.3.5.1) has proven to be an important fungicidal target, and the inhibition of SDH is useful in the treatment of plant pathogens. The discovery of a novel active SDH inhibitor is of high value. Herein, we disclose the discovery of a potent, highly active inhibitor as a fungicide candidate by using a computational substitution optimization method, a fast drug design method developed in our laboratory. The greenhouse experiments showed that compound 17c exhibited high protective activity against south corn rust, soybean rust (SBR), and rice sheath blight at a very low dosage of 0.781 mg/L. Moreover, the field trials indicated that compound 17c is comparable to and even better than commercial fungicides against SBR and cucumber powdery mildew at 50 mg/L concentration. Most surprisingly, compound 17c resulted to be strictly better in curative activity than the commercial fungicide benzovindiflupyr. The computation results indicated that 17c could form another hydrogen bond with C_S42 and then lead to strong van der Waals and electronic interactions with SDH. Our results suggested that 17c is a potential fungicide candidate for SDH.

BACKGROUND Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by systemic involvement and multiple autoantibodies in the serum. Patients with protein C (PC) and protein S (PS) deficiency are prone to thrombosis. In contrast, patients with primary hyperfibrino-lysis tend to bleed. CASE SUMMARY A 52-year-old female patient with bilateral pleural effusion was diagnosed with "tuberculous pleurisy" and treated with anti-tuberculosis drugs and prednisone. The coagulation-related laboratory results showed decreased fibrinogen, PC activity, PS activity, and antithrombin Ш activity. The immune-related laboratory results showed positive antinuclear antibody, anti-Smith antibody, anticardiolipin antibody (ACL), anti-β2-glycoprotein I antibody (aβ2GPI) and direct Coomb’s test and decreased complement 3 and complement 4. Thoracoscopy was performed and bloody pleural fluid was drained. Pathology of the pleural biopsy showed lymphocytes, plasma cells, and a few eosinophils in adipose and fibrous connective tissue. Results of whole exome sequencing of blood showed no genetic mutations suggesting the presence of hereditary hematological diseases. The patient was finally diagnosed with SLE and primary hyperfibrinolysis, and was treated with prednisolone, hydroxychloroquine, and compound cyclophosphamide. CONCLUSION PC and PS deficiency in SLE might be related to ACL and aβ2GPI. SLE and primary hyperfibrinolysis can coexist in one patient, with both a risk of thrombosis and a risk of bleeding.

Two mononuclear DyIII single-molecule magnets (SMMs) with C2v coordination symmetry were synthesized. Both of them have strong uniaxial magnetic anisotropy with high effective energy barriers for magnetization reversal over 600 K and hysteresis loops opened up to 8 K, and they are by far the best lanthanide SMMs with a C2v symmetry coordination environment. Ab initio calculations reveal that the crystal field around the DyIII ion is the key factor determining the magnetization dynamics of the SMMs. The multidentate ligand controls the orientation of the main magnetic axes which are both nearly parallel to the phenoxide Dy–O bonds and perpendicular to the equatorial plane with relatively weak coordination by the four nitrogen atoms and one Cl− or Br− anion. The variation of the terminal Cl− or Br− anion slightly influences the magnetization dynamics. This work provides the fundamentals to govern the SMM behavior of lanthanide complexes with a relatively low coordination symmetry of the lanthanide center.

This paper is concerned about a diffusive degenerate predator–prey model with Beddington–DeAngelis functional response subject to homogeneous Neumann boundary condition. First, the global bifurcati...

Benzophenone (BP) is an ultraviolet filter (UVF) widely used in personal care products such as sunscreens and cosmetics. Excessive exposure to BP-type UVFs is a potential threat to human's health because of their endocrine-disrupting activity. Water stability of lanthanide compounds is crucial when they serve as luminescent sensors because of the practicality and recyclability. In this study, a water-stable luminescent Zn-Tb heterometallic coordination polymer was rationally designed and synthesized for rapid detection of BP. This material showed a high quenching effect, excellent selectivity, and fast response toward BP.

To investigate the effect of Rheb1 in the development of mouse megakaryocyte-erythroid progenitor cells and its related mechanism.Rheb1 was specifically knocked-out in the hematopoietic system of Vav1-Cre;Rheb1After Rheb1 was knocked out, the development and stress response ability of megakaryocyte-erythroid progenitor cells in mice were weaken and the differentiation ability of megakaryocyte-erythroid progenitor cells in vitro was weaken. Moreover, the expression of GATA-1 of megakaryocyte-erythroid progenitor cells was decreased. Further, rapamycin could inhibit the differentiative capacity of megakaryocyte-erythroid progenitor cells in vitro.Rheb1 can regulate the development of megakaryocyte-erythroid progenitor cells probably through the mTOR signaling pathway in mice.Rheb1在小鼠巨核-红系多能性干细胞发育中的作用.研究Rheb1基因在小鼠巨核-红系多能性干细胞发育成熟中的作用及相关的机制.利用Vav-Cre在造血系统中特异性敲除小鼠Rheb1（Vav1-Cre;Rheb1Rheb1敲除后，小鼠骨髓中红系细胞发育受抑且应激能力减弱，小鼠骨髓中巨核-红系多能性干细胞体外克隆形成能力减弱，GATA-1的表达水平降低；雷帕霉素可以抑制野生型小鼠骨髓中巨核-红系多能性干细胞体外克隆的形成.Rheb1基因在小鼠巨核-红系多能性干细胞发育中具有重要的调控作用，Rheb1可能通过mTOR信号通路调控小鼠巨核-红系多能性干细胞发育.

Danggui Buxue Decoction is a classic prescription of Qi and blood tonification, which is mainly applied in treating fatigue, internal damage Qi weakness, blood deficiency, and outward going of floating Yang. Modern pharmacology shows that it can promote hematopoiesis, regulate immunity, and protect heart and cerebral vessels. The prescription, often used for the treatment of anemia and other diseases in clinic, is composed of Astragali Radix and Angelicae Sinensis Radix at a dosage ratio of 5∶1. It is a modern compound prescription for invigorating Qi and generating blood. Based on the review of the chemical constituents, pharmacological effects, and clinical applications of Danggui Buxue Decoction, its Q-marker was predicted and analyzed according to thequot;five principlesquot; of Chinese medicine Q-marker--quality transmissibility and traceability, ingredient specificity, component validity, component measurabi-lity, and formula compatibility environment. The results suggested that calycosin, calycosin-7-O-β-D-glucoside, formononetin, ononin, astragaloside A, ferulic acid, and ligustilide could be used as Q-markers of Danggui Buxue Decoction, which provides reference for establishing the quality system of Danggui Buxue Decoction.

In this study, the antityrosinase and antioxidant activities of four guanidine compounds (GCs), including guanylthiourea (GT), guanidine thiocyanate (GTC), phenylguanidine (PG), and phenethyldiguanide (PTDG), were investigated. The results showed that the GCs reduced the monophenolase and diphenolase activities of tyrosinase. The IC50 values of GT, GTC, PG, and PTDG were 0.27, 3.53, 6.68, and 5.18 mM for monophenolase and 0.23, 3.24, 3.97 and 2.50 mM for diphenolase, respectively. The inhibition of diphenolase activity was reversible for the four GCs. The inhibition types of GT and PTDG were competitive, while those of GTC and PG were mixed. FRAP, ABTS, DPPH, and DNA damage protection assays revealed that only GT possessed significant antioxidant activity. Furthermore, GT was found to decrease the melanin content and expression of TYR, MITF and DCT in both B16F10 cells and zebrafish. Overall, our results indicated that GT can inhibit tyrosinase activity in vitro, which suggests that these GCs are potential candidates for novel small-molecule tyrosinase inhibitors and that GT could have broader application prospects.

The marine natural product neopeltolide was isolated from a deep-water sponge specimen of the family Neopeltidae. Neopeltolide has been proven to be a new type of inhibitor of the cytochrome bc1 complex in the mitochondrial respiration chain. However, its detailed inhibition mechanism has remained unknown. In addition, neopeltolide is difficult to synthesize because of its very complex chemical structure. In the present work, the binding mode of neopeltolide was determined for the first time by integrating molecular docking, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area calculations, which showed that neopeltolide is a Qo site inhibitor of the bc1 complex. Then, according to guidance via inhibitor-protein interaction analysis, structural modification was carried out with the aim to simplify the chemical structure of neopeltolide, leading to the synthesis of a series of new neopeltolide derivatives with much simpler chemical structures. The calculated binding energies (Δ Gcal) of the newly synthesized analogues correlated very well ( R2 = 0.90) with their experimental binding free energies (Δ Gexp), which confirmed that the computational protocol was reliable. Compound 45, bearing a diphenyl ether fragment, was successfully designed and synthesized as the most potent candidate (IC50 = 12 nM) against porcine succinate cytochrome c reductase. The molecular modeling results indicate that compound 45 formed a π-π interaction with Phe274 and two hydrogen bonds with Glu271 and His161. The present work provides a new starting point for future fungicide discovery to overcome the resistance that the existing bc1 complex inhibitors are facing.

This paper deals with a predator-prey model with Beddington-DeAngelis functional response, in which a protection zone is created for the prey species. Whether the combination of the protection zone and the Beddington-DeAngelis functional response can yield new results or not is of interest. The result reveals that they jointly produce a new critical value, which is smaller than that determined by either the protection zone or the functional response singly. As a result, rather different stationary patterns can be found and the combined effects are very prominent. Then the effect of the parameter $k$ in the Beddington-DeAngelis functional response is studied. The result deduces that as $k$ is large enough, there exists a unique positive stationary solution and it is linearly stable except a special case. Actually, we can obtain that the positive stationary solution is globally asymptotically stable.

The energy barrier and hysteresis temperature in two benchtop-stable D5h-symmetry HoIII single-ion magnets were significantly enhanced via the variation of the halogen anion. The coexistence of a high energy barrier of 418 K and hysteresis temperature of 15 K was observed in the bromide-ion containing HoIII single-ion magnet.

Highly enantiopure and bioactive δ-valerolactones and pyrazolones, bearing α-all-carbon quaternary stereocentres, were successfully and sequentially prepared via a one-pot procedure starting from readily available, inexpensive materials, catalysed by a new chiral squaramide under mild reaction conditions. An organocatalytic Michael reaction afforded the valerolactones, while a one-pot Michael-hydrazinolysis-imidization cascade yielded the pyrazolones. This procedure is economically efficient and environmentally benign.

The discovery of novel succinate dehydrogenase inhibitors (SDHIs) has attracted great attention worldwide. Herein, a fragment recombination strategy was proposed to design new SDHIs by understanding the ligand-receptor interaction mechanism of SDHIs. Three fragments, pyrazine from pyraziflumid, diphenyl-ether from flubeneteram, and a prolonged amide linker from pydiflumetofen and fluopyram, were identified and recombined to produce a pyrazine-carboxamide-diphenyl-ether scaffold as a new SDHI. After substituent optimization, compound 6y was successfully identified with good inhibitory activity against porcine SDH, which was about 2-fold more potent than pyraziflumid. Furthermore, compound 6y exhibited 95% and 80% inhibitory rates against soybean gray mold and wheat powdery mildew at a dosage of 100 mg/L in vivo assay, respectively. The results of the present work showed that the pyrazine-carboxamide-diphenyl-ether scaffold could be used as a new starting point for the discovery of new SDHIs.

Suanzaoren Decoction is a classic prescription for nourishing the heart and liver, nourishing blood and tranquilizing the mind. It has the functions of sedation and hypnosis, anti-anxiety, anti-depression, anti-convulsion and so on. Modern clinic is mostly used to treat different types of insomnia, depression, neurasthenia, tension headache and vertigo. In this paper, the chemical consti-tuents, pharmacological effects and clinical application of Suanzaoren Decoction are reviewed. Based on this, the quality marker(Q-marker) of Suanzaoren Decoction was predicted and analyzed according to thequot;five principlesquot; of Q-marker of traditional Chinese medicine--transmission and traceability, specificity, effectiveness, measurability and compatibility environment of compound prescriptions. The results indicated that jujuboside, spinosin, ferulic acid, senkyunolide Ⅰ, sarsasapogenin, mangiferin, liquiritoside and glycyrrhizic acid were predicted and analyzed, and those can be used as Q-markers of Suanzaoren Decoction. Subsequently, the above components can be selected as indicators to control and evaluate the quality of Suanzaoren Decoction and its preparations, and establish a quality traceability system.

Neopeltolide, a natural product isolated from deep-water sponge specimen of the family neopeltidae, has been proven to be a novel inhibitor of cytochrome bc

Succinate-cytochrome c reductase (SCR) is composed of a mixture of mitochondrial complex II (succinate-ubiquinone oxidoreductase) and complex III (cytochrome bc1 complex). Meanwhile, complexes II and III are two promising targets of numerous antibiotics and fungicides. With an aim to identify new lead structures for SCR, complex II or III, a new series of 4-aryloxy-N-arylanilines were synthesized by introducing a 4-aryloxy phenyl group as one of the aryl groups in diaryl amines. With the economic Cu(OAc)2·H2O as the optimal copper promoter, a simple and facile protocol was utilized to afford 24 target products in 56-93% yields. Furthermore, extensive screening results suggested variable inhibitory activities of these compounds against SCR. Exceptionally, compounds 7k-7n showed excellent inhibition potency with their IC50 values in the nanomolar range, demonstrating higher potency than the commercial controls (penthiopyrad and azoxystrobin) by over one order of magnitude.

In this paper, we consider a reaction–diffusion system describing a three-species Lotka–Volterra food chain model with homogeneous Dirichlet boundary conditions. By regarding the birth rate of prey r 1 as a bifurcation parameter, the global bifurcation of positive steady-state solutions from the semi-trivial solution set is obtained via the bifurcation theory. The results show that if the birth rate of mid-level predator and top predator are located in the regions 0 r 2 λ 1 a 23 u 3 r 3 and r 3 > λ 1 , respectively. Then the three species can co-exist provided the birth rate of prey exceeds a critical value. Moreover, an explicit expression of coexistence steady-state solutions is constructed by applying the implicit function theorem. It is demonstrated that the explicit coexistence steady-state solutions is locally asymptotically stable.

In this paper, we study the steady-state problem of an S-K-T competition model with a spatially degenerate intraspecific competition coefficient. First, the global bifurcation continuum of positive steady-state solutions from its semitrivial steady-state solution is given, which depends on the spatial heterogeneity and cross-diffusion. Second, two limiting systems are derived as the cross-diffusion coefficient tends to infinity. Moreover, we demonstrate the existence of positive steady-state solutions near the two limiting systems, and show which one of the limiting systems characterizes the positive steady-state solution.

Two tetrahedral nickel(II) cages [Ni4L6]8+ (1 and 2) with large rigid aromatic ligands were synthesized and investigated for their G-quadruplex DNA binding abilities. The crystal structure of cage 1 confirmed [Ni4(L1)6]8+ tetrahedral formulation. The nickel center coordinated with N6 coordination environments form a distorted octahedral geometry, and the average Ni−Ni bond length is 12.89 A. It is exciting that cages 1-2 showed considerably effective stabilization of antiparallel G-quadruplex (∆Tm = 39.0940.90 °C). The subsequent G-quadruplex binding studies on the other analogous cages 3-6 were performed to further explore the impact factors of central metal ion and overall charge on interaction with G-quadruplex DNA. The corresponding iron(II) cages [Fe4(L1)6]8+ (3) and [Fe4(L2)6]8+ (4) exhibited lower stabilization effect on G-quadruplex DNA (∆Tm = 18.3324.80 °C), and the anionic tetrahedral cages [Fe4(L3)6]4- (5) and [Ni4(L3)6]4- (6) turned out to be inefficient for stabilizing G4 DNA (∆Tm < 1 °C). Moreover, the remarkable stabilization of G-quadruplex DNA induced by rigid cages 1-2 represent a significant improvement as compared to reported flexible Ni4 cages. These results indicated that central metal ion, overall charge and structural rigidity of tetrahedral cages played critical roles in G-quadruplex stabilization, which will provide new insight into the interactions between tetrahedral cages and G-quadruplex DNA.

AgNWs@SCO nanocomposites were constructed by in situ growing spin-crossover (SCO) nanoparticles on silver nanowires (AgNWs). The obtained AgNWs@[Fe(Htrz)2(trz)](BF4) (AgNWs@SCO-1) and AgNWs@Fe(pz)[Pt(CN)4] (AgNWs@SCO-2) nanomaterials were characterized by FT-IR, PXRD, Raman spectroscopy, SEM and TEM. SEM images show that SCO NPs grow on the surface of the AgNWs, and their size and shape can be tuned by controlling the amount of added iron(II) salt. The magnetic measurements exhibit hysteresis loops with 45 K (Tc↑ = 385 K, Tc↓ = 340 K) for SCO-1 and 31 K (Tc↑ = 290 K, Tc↓ = 259 K) for SCO-2. It is interesting that both AgNWs@SCO nanocomposites retain spin-crossover behaviour with hysteresis loops with 50 K (Tc↑ = 395 K and Tc↓ = 345 K) for AgNWs@SCO-1 and 34 K (Tc↑ = 289 K and Tc↓ = 255 K) for AgNWs@SCO-2. The hot pressing method is used to transfer AgNWs@SCO nanocomposites to flexible PET substrates for a four-probe conductivity test. The conductivities of AgNWs@SCO-1 and AgNWs@SCO-2 are consistent with that of the individual AgNWs over the 100–350 K range, indicating that AgNWs@SCO nanocomposites exhibit good conductivity. The combination of both spin-crossover properties and conductive properties in AgNWs@SCO materials provides a great prospect for their application in devices.

Two one-dimensional nitronyl nitroxide radical (NITR)-bridged lanthanide chain compounds, namely [Tb(hfac)

The ordering of polar hydrogen bonds may break space inversion symmetry and induce ferroelectricity or antiferroelectricity. This process is usually immune to external magnetic fields so that magnetic control of hydrogen bonds is very challenging. Here we demonstrate that the ordering of hydrogen bonds in the metal-organic frameworks $[{({\mathrm{CH}}_{3})}_{2}{\mathrm{NH}}_{2}]M{(\mathrm{HCOO})}_{3}$ ($M=\mathrm{Fe}$, Co) can be manipulated by applying magnetic fields. After cooling in a high magnetic field, the order-disorder transition of hydrogen bonds shifts to a lower or higher temperature, depending on antiferroelectricity or ferroelectricity induced by hydrogen bond ordering. Besides, the order-disorder transition leads to a giant thermal expansion, exceeding $\ensuremath{\sim}3.5\ifmmode\times\else\texttimes\fi{}{10}^{4}$ and $\ensuremath{\sim}2\ifmmode\times\else\texttimes\fi{}{10}^{4}\text{ }\text{ }\mathrm{ppm}$ for $M=\mathrm{Fe}$ and Co, respectively, which is much higher than that of inorganic ferroelectrics. The influence of magnetic field on hydrogen bond ordering is discussed in terms of the magnetoelastic coupling.