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"Shi, Yan-Ni"
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إدارة الأزمات في زمن الأوبئة : مقالات لـ 56 عالما في الإدارة
يضم هذا الكتاب خلاصة تجارب وعصارة أفكار 56 عالما، هم من أبرز علماء الإدارة في الصين، وقد حملوا على عاتقهم مسؤولية قيادة المؤسسات الصينية لسنوات عديدة، وهو كتاب مرجعي لكل المؤسسات على المستوى العالمي والتي إن حدث لها ضرر في فترات الأزمات أو الأوبئة، فلن يتوقف هذا الضرر عند ملاكها أو المنتفعين منها، بل سيمتد أثره إلى قطاعات عريضة من العمالة، وسيضرب القوة الإنتاجية ولا سيما الصادرات والواردات وغيرها من الموارد. ومن ثم فهم محاربون على الخطوط الأولى، مثلهم مثل الأطباء في أزمة انتشار فيروس كورونا المستجد، وإن كان مجال تخصص كل مختلفا منهم عن الآخر، ففريق منهم ينقذ حياة الناس، بينما الفريق الآخر ينقذ أقواتهم. ولغة الكتاب لغة سهلة وبسيطة، تنطلق أفكاره من مواقف عامة وليست من مواقف خاصة محددة، ومن هنا تعد أفكاره صالحة للتطبيق على المؤسسات الصغيرة والمتوسطة في كل مكان، والتي أصبح لزاما عليها أن تلجأ للابتكار والإبداع إن أرادت الاستمرار على قيد الحياة، وبات عليها أن تبحث وسط ركام الأزمة عن الإيجابيات التي يمكن أن تهب لها حياة جديدة وسبلا مبتكرة للخلاص.
Book
Modification and de novo design of non-ribosomal peptide synthetases using specific assembly points within condensation domains
Non-ribosomal peptide synthetases (NRPSs) are giant enzyme machines that activate amino acids in an assembly line fashion. As NRPSs are not restricted to the incorporation of the 20 proteinogenic amino acids, their efficient manipulation would enable microbial production of a diverse range of peptides; however, the structural requirements for reprogramming NRPSs to facilitate the production of new peptides are not clear. Here we describe a new fusion point inside the condensation domains of NRPSs that results in the development of the exchange unit condensation domain (XUC) concept, which enables the efficient production of peptides, even containing non-natural amino acids, in yields up to 280 mg l
. This allows the generation of more specific NRPSs, reducing the number of unwanted peptide derivatives, but also the generation of peptide libraries. The XUC might therefore be suitable for the future optimization of peptide production and the identification of bioactive peptide derivatives for pharmaceutical and other applications.
Journal Article
Integrating genomics and metabolomics for scalable non-ribosomal peptide discovery
Non-Ribosomal Peptides (NRPs) represent a biomedically important class of natural products that include a multitude of antibiotics and other clinically used drugs. NRPs are not directly encoded in the genome but are instead produced by metabolic pathways encoded by biosynthetic gene clusters (BGCs). Since the existing genome mining tools predict many putative NRPs synthesized by a given BGC, it remains unclear which of these putative NRPs are correct and how to identify post-assembly modifications of amino acids in these NRPs in a blind mode, without knowing which modifications exist in the sample. To address this challenge, here we report NRPminer, a modification-tolerant tool for NRP discovery from large (meta)genomic and mass spectrometry datasets. We show that NRPminer is able to identify many NRPs from different environments, including four previously unreported NRP families from soil-associated microbes and NRPs from human microbiota. Furthermore, in this work we demonstrate the anti-parasitic activities and the structure of two of these NRP families using direct bioactivity screening and nuclear magnetic resonance spectrometry, illustrating the power of NRPminer for discovering bioactive NRPs.
Journal Article
Global analysis of biosynthetic gene clusters reveals conserved and unique natural products in entomopathogenic nematode-symbiotic bacteria
Microorganisms contribute to the biology and physiology of eukaryotic hosts and affect other organisms through natural products. Xenorhabdus and Photorhabdus (XP) living in mutualistic symbiosis with entomopathogenic nematodes generate natural products to mediate bacteria-nematode-insect interactions. However, a lack of systematic analysis of the XP biosynthetic gene clusters (BGCs) has limited the understanding of how natural products affect interactions between the organisms. Here we combine pangenome and sequence similarity networks to analyse BGCs from 45 XP strains that cover all sequenced strains in our collection and represent almost all XP taxonomy. The identified 1,000 BGCs belong to 176 families. The most conserved families are denoted by 11 BGC classes. We homologously (over)express the ubiquitous and unique BGCs and identify compounds featuring unusual architectures. The bioactivity evaluation demonstrates that the prevalent compounds are eukaryotic proteasome inhibitors, virulence factors against insects, metallophores and insect immunosuppressants. These findings explain the functional basis of bacterial natural products in this tripartite relationship.
Journal Article
Ultralow platinum-loading PtPdRu@PtRuIr/C catalyst with excellent CO tolerance and high performance for the methanol oxidation reaction
Carbon-supported PtPdRuIr, Pd@PtRuIr, PtPd@PtRuIr, and PtPdRu@PtRuIr catalysts were prepared by a colloidal method and their catalytic activities to the methanol oxidation reaction in the acidic media were extensively investigated at room temperature. The catalysts were characterized by transmission electron microscopy and X-ray diffraction techniques, and their electrochemical behavior was evaluated by the cyclic voltammetry. The PtPdRu@PtRuIr/C catalyst is found to yield much higher electrocatalytic activity than the other ones and the commercial catalyst. For example, the Pt metal mass-specific activity of this PtPdRu@PtRuIr/C（Pt content 10 wt%,1.7 mAácm-2ámg-1） electrocatalyst is ＊3-fold higher than that of the commercial JM 40 % Pt/C（0.6 mAácm-2ámg-1）electrocatalysts, and the If/Ib ratio of PtPdRu@PtRuIr/C is1.6, which is higher than that of the JM 40 % Pt/C（0.9）. The improvement may result from the high dispersion of the active metal catalyst and the synergistic effect between the PtRuIr and PtPdRu layers. It is thus concluded that the pseudo-core-shell structure could significantly improve the methanol electro-oxidation activity and CO tolerance of the electrocatalyst.
Journal Article
Global analysis of biosynthetic gene clusters reveals conserved and unique natural products in entomopathogenic nematode-symbiotic bacteria
Microorganisms contribute to the biology and physiology of eukaryotic hosts and affect other organisms through natural products. Xenorhabdus and Photorhabdus (XP) living in mutualistic symbiosis with entomopathogenic nematodes produce a myriad of natural products to mediate bacteria-nematode-insect interactions. However, a lack of systematic analysis of the biosynthetic gene clusters (BGCs) has limited the understanding of how natural products justify the bacterial niche specificity. Here we combine pangenome and sequence similarity network to analyze BGCs from 45 XP species. The identified 1,000 BGCs belong to 176 families, over half of which are unknown. Eleven BGCs represent the most conserved families. We then homologously express the ubiquitous and unique BGCs and identify compounds featuring unusual architectures. The bioactivity evaluation demonstrates that the prevalent compounds are eukaryotic proteasome inhibitors, insect virulence factors, or insect immune suppressors. These findings account for the functional basis of bacterial natural products in this tripartite relationship. Competing Interest Statement Y.-M.S., W.K., M.G., and H.B.B. are inventors on a patent application covering the structure and use of IOC, which has been filed by Max Planck Society, Technical University of Munich, and Goethe University Frankfurt. Y.-M.S., D.A., J.J.C., and H.B.B. are inventors on a patent application covering the structure and use of rhabdobranin, which has been filed by Max Planck Society. The other authors declare no competing interests.
Paper
The Chemical Structure of Widespread Microbial Aryl Polyene Lipids
Abstract Biosynthetic gene clusters (BGC) involved in aryl polyene (APE) biosynthesis are supposed to represent the most widespread BGC in the bacterial world.[1–3] Still, only hydrolysis products[4–8] and not the full-length product(s) have been identified, hindering studies on their biosynthesis and natural function. Here, we apply subsequent chromatographic separations to purify the aryl polyene-containing lipids (APELs) from the entomopathogenic bacterium Xenorhabdus doucetiae. Structure elucidation using a combination of isotope labeling, nuclear magnetic resonance techniques, and tandem mass spectrometry reveals an array of APELs featuring an all-trans C26:5 conjugated fatty acyl and a galactosamine-phosphate-glycerol moiety. In combination with extensive genetic studies, this research broadens the bacterial natural product repertoire and paves the way for future functional characterization of this almost universal microbial compound class. Due to their protective function against reactive oxygen species,[5,9] APELs might be important for virulence or symbiosis, mediating organismic interactions in several ecological niches. Competing Interest Statement The authors have declared no competing interest.
Paper
Focused natural product elucidation by prioritizing high-throughput metabolomic studies with machine learning
Bacteria of the genera Photorhabdus and Xenorhabdus produce a plethora of natural products to support their similar symbiotic lifecycles. For many of these compounds, the specific bioactivities are unknown. One common challenge in natural product research when trying to prioritize research efforts is the rediscovery of identical (or highly similar) compounds from different strains. Linking genome sequence to metabolite production can help in overcoming this problem. However, sequences are typically not available for entire collections of organisms. Here we perform a comprehensive metabolic screening using HPLC-MS data associated with a 114-strain collection (58 Photorhabdus and 56 Xenorhabdus) from across Thailand and explore the metabolic variation among the strains, matched with several abiotic factors. We utilize machine learning in order to rank the importance of individual metabolites in determining all given metadata. With this approach, we were able to prioritize metabolites in the context of natural product investigations, leading to the identification of previously unknown compounds. The top three highest-ranking features were associated with Xenorhabdus and attributed to the same chemical entity, cyclo(tetrahydroxybutyrate). This work addresses the need for prioritization in high-throughput metabolomic studies and demonstrates the viability of such an approach in future research.
Paper
Ethanol inhibits histaminergic neurons in mouse tuberomammillary nucleus slices via potentiating GABAergic transmission onto the neurons at both pre- and postsynaptic sites
Aim： Ethanol, one of the most frequently used and abused substances in our society, has a profound impact on sedation. However, the neuronal mechanisms underlying its sedative effect remain unclear. In this study, we investigated the effects of ethanol on histaminergic neurons in the tuberomammillary nucleus （TMN）, a brain region thought to be critical for wakefulness.
Methods： Coronal brain slices （250 pm thick） containing the TMN were prepared from GAD67-GFP knock-in mice. GAD67-GFP was used to identify histaminergic neurons in the TMN. The spontaneous firing and membrane potential of histaminergic neurons, and GABAergic transmission onto these neurons were recorded using whole-cell patch-clamp recordings. Drugs were applied through superfusion.
Results： Histaminergic and GAD67-expressing neurons in the TMN of GAD67-GFP mice were highly co-localized. TMN GFP-positive neurons exhibited a regular spontaneous discharge at a rate of 2-4 Hz without burst firing. Brief superfusion of ethanol （64, 190, and 560 mmol/L） dose-dependently and reversibly suppressed the spontaneous firing of the neurons in the TMN; when synaptic transmission was blocked by tetrodotoxin （1 μmol/L）, ethanol caused hyperpolarization of the membrane potential. Furthermore, superfusion of ethanol markedly increased the frequency and amplitude of spontaneous and miniature inhibitory postsynaptic currents （slPSCs and mlPSCs）, which were abolished in the presence of the GABAA receptor antagonist bicuculline （20 μmol/L）. Finally, ethanolmediated enhancement of slPSCs and mlPSCs was significantly attenuated when the slices were pretreated with the GABAB agonist baclofen （30 μmoVL）.
Conclusion： Ethanol inhibits the excitability of histaminergic neurons in mouse TMN slices, possibly via potentiating GABAergic transmission onto the neurons at both pre- and postsynaptic sites.
Journal Article