Rational Design of Novel Phosphoinositide 3‐Kinase Gamma (PI3Kγ) Selective Inhibitors: A Computational Investigation Integrating 3D‐QSAR,Molecular Docking and Molecular Dynamics Simulation

Phosphoinositide 3‐kinase gamma (PI3Kγ) draws an increasing attention due to its link with deadly cancer, chronic inflammation and allergy. But the development of PI3Kγ selective inhibitors is still a challenging endeavor because of the high sequence homology with the other PI3K isoforms. In order to acquire valuable information about the interaction mechanism between potent inhibitors and PI3Kγ, a series of PI3Kγ isoform‐selective inhibitors were analyzed by a systematic computational method, combining 3D‐QSAR, molecular docking, molecular dynamic (MD) simulations, free energy calculations and decomposition. The general structure–activity relationships were revealed and some key residues relating to selectivity and high activity were highlighted. It provides precious guidance for rational virtual screening, modification and design of selective PI3Kγ inhibitors. Finally, ten novel inhibitors were optimized and P10 showed satisfactory predicted bioactivity, demonstrating the feasibility to develop potent PI3Kγ inhibitors through this computational modeling and optimization.     

Sequentially Deposited versus Conventional Nonfullerene Organic Solar Cells: Interfacial Trap States,Vertical Stratification,and Exciton Dissociation

Bulk heterojunction (BHJ) nonfullerene organic solar cells prepared from sequentially deposited donor and acceptor layers (sq‐BHJ) have recently been shown to be highly efficient, environmentally friendly, and compatible with large area and roll‐to‐roll fabrication. However, the related photophysics at donor‐acceptor interface and the vertical heterogeneity of donor‐acceptor distribution, critical for exciton dissociation and device performance, have been largely unexplored. Herein, steady‐state and time‐resolved optical and electrical techniques are employed to characterize the interfacial trap states. Correlating with the luminescent efficiency of interfacial states and its nonradiative recombination, interfacial trap states are characterized to be about 40% more populated in the sq‐BHJ devices than the as‐cast BHJ (c‐BHJ), which probably limits the device voltage output. Cross‐sectional energy‐dispersive X‐ray spectroscopy and ultraviolet photoemission spectroscopy depth profiling directly visualize the donor–acceptor vertical stratification with a precision of 1–2 nm. From the proposed “needle” model, the high exciton dissociation efficiency is rationalized. This study highlights the promise of sequential deposition to fabricate efficient solar cells, and points toward improving the voltage output and overall device performance via eliminating interfacial trap states.     

Grey mould of strawberry,a devastating disease caused by the ubiquitous necrotrophic fungal pathogen Botrytis cinerea

The fungal pathogen Botrytis cinerea causes grey mould, a commercially damaging disease of strawberry. This pathogen affects fruit in the field, storage, transport and market. The presence of grey mould is the most common reason for fruit rejection by growers, shippers and consumers, leading to significant economic losses. Here, we review the biology and epidemiology of the pathogen, mechanisms of infection and the genetics of host plant resistance. The development of grey mould is affected by environmental and genetic factors; however, little is known about how B. cinerea and strawberry interact at the molecular level. Despite intensive efforts, breeding strawberry for resistance to grey mould has not been successful, and the mechanisms underlying tolerance to B. cinerea are poorly understood and under-investigated. Current control strategies against grey mould include pre- and postharvest fungicides, yet they are generally ineffective and expensive. In this review, we examine available research on horticultural management, chemical and biological control of the pathogen in the field and postharvest storage, and discuss their relevance for integrative disease management. Additionally, we identify and propose approaches for increasing resistance to B. cinerea in strawberry by tapping into natural genetic variation and manipulating host factors via genetic engineering and genome editing.     

E0771 and 4T1 murine breast cancer cells and interleukin 6 alter gene expression patterns but do not induce browning in cultured white adipocytes

Breast cancer remains a substantial clinical problem worldwide, and cancer-associated cachexia is a condition associated with poor prognosis in this and other malignancies. Adipose tissue is involved in the development and progression of cancer-associated cachexia, but its various roles and mechanisms of action are not completely defined, especially as it relates to breast cancer. Interleukin 6 has been implicated in several mechanisms contributing to increased breast cancer tumorigenesis, as well as a net-negative energy balance and cancer-associated cachexia via adipose tissue remodeling in other models of cancer; however, its potential role in breast cancer-associated white adipose browning has not been explored. In this study, we demonstrate localized white adipose tissue browning in a spontaneous model of murine mammary cancer. We then used an in vitro murine adipocyte culture system with the E0771 and 4T1 cell lines as models of breast cancer. We demonstrate that while the E0771 and 4T1 secretomes and cross-talk with white adipocytes alter white adipocyte mRNA expression, they do not directly induce white adipocyte browning. Additionally, we show that neither exogenous administration of interleukin 6 alone or with its soluble receptor directly induce white adipocyte browning. Together, these results demonstrate that neither the E0771 or 4T1 murine breast cancer cell lines, nor interleukin 6, directly cause browning of cultured white adipocytes. This suggests that their roles in adipose tissue remodeling are more complex and indirect in nature.     

Structural characterization and immunological activity of two cold-water extractable polysaccharides from Cistanche deserticola Y. C. Ma

Two major polysaccharide fractions, CDA-1A and CDA-3B, were isolated from the cold-water extract of Cistanche deserticola Y. C. Ma, a holoparasitic plant and a valuable traditional Chinese medicine, using anion-exchange chromatography on DEAE-cellulose and gel-permeation chromatography on Sephacryl S-300 and Sephadex G-150. Their major structural features were elucidated using component and linkage analyses, periodate oxidation, Smith degradation, partial acid hydrolysis, and NMR spectroscopy. The results indicated that CDA-1A is an alpha-(1-->4)-D-glucan with alpha-(1-->6)-linked branches attached to the O-6 of branch points and that CDA-3B is an RG-I polysaccharide containing a typical rhamnogalacturonan backbone and arabinogalactan or arabinan branches. Bioactivity tests showed that CDA-1A is inert for T-cell proliferation stimulation but active for B-cell proliferation, while CDA-3B is potent for the stimulation of both T- and B-cell proliferation.     

Identification and characterization of DUSP27, a novel dual-specific protein phosphatase

A novel human dual-specific protein phosphatase (DSP), designated DUSP27, is here described. The DUSP27 gene contains three exons, rather than the predicted 4-14 exons, and encodes a 220 amino acid protein. DUSP27 is structurally similar to other small DSPs, like VHR and DUSP13. The location of DUSP27 on chromosome 10q22, 50 kb upstream of DUSP13, suggests that these two genes arose by gene duplication. DUSP27 is an active enzyme, and its kinetic parameters and were determined. DUSP27 is a cytosolic enzyme, expressed in skeletal muscle, liver and adipose tissue, suggesting its possible role in energy metabolism.     

柴达木沙漠链霉菌S10T阿糖腺苷的大孔树脂分离工艺优化与结构鉴定

为了获得具有药用价值的活性天然产物,采用4种大孔吸附树脂对柴达木沙漠链霉菌（Streptomyces qaidemensis）S10^T发酵液进行静态吸附和解吸实验,优化分离工艺。结果显示,AB-8型树脂具有良好的吸附和解吸性能,该树脂对柴达木沙漠链霉菌S10^T发酵液中的活性天然产物吸附工艺为发酵液pH值9,吸附时间4 h,洗脱液70%甲醇溶液。经正向硅胶、反相硅胶和葡聚糖凝胶Sephadex LH-20分离得到了一个化合物,¹H-NMR和¹³C-NMR结合高分辨质谱（LC-HR-MS）鉴定该化合物为阿糖腺苷（vidarabine）,是一种具有抗病毒活性的核苷类抗生素,并简单探究了其在柴达木沙漠链霉菌中的生物合成过程。     

Angiotensin-converting enzyme inhibitors attenuated advanced glycation end products-induced renal tubular hypertrophy via enhancing nitric oxide signaling

Advanced glycation end products (AGE) and angiotensin II were closely correlated with the progression of diabetic nephopathy (DN). Nitric oxide (NO) is a protective mediator of renal tubular hypertrophy in DN. Here, we examined the molecular mechanisms of angiotensin-converting enzyme inhibitor (ACEI) and NO signaling responsible for diminishing AGE-induced renal tubular hypertrophy. In human renal proximal tubular cells, AGE decreased NO production, inducible NOS activity, guanosine 3′,5′-cyclic monophosphate (cGMP) synthesis, and cGMP-dependent protein kinase (PKG) activation. All theses effects of AGE were reversed by treatment with ACEIs (captopril and enalapril), the NO donor S-nitroso-N-acetylpenicillamine (SNAP), and the PKG activator 8-para-chlorophenylthio-cGMPs (8-pCPT-cGMPs). In addition, AGE-enhanced activation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) were clearly reduced by captopril, enalapril, SNAP, and 8-pCPT-cGMPs. The abilities of ACEIs and NO/PKG activation to inhibit AGE-induced hypertrophic growth were verified by the observation that captopril, enalapril, SNAP, and 8-pCPT-cGMPs decreased protein levels of fibronectin, p21 ^Waf1/Cip1, and receptor for AGE. The results of the present study suggest that ACEIs significantly reduced AGE-increased ERK/JNK/p38 MAPK activation and renal tubular hypertrophy partly through enhancement of the NO/PKG pathway.