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Chemistry-led investigations into the mode of action of NAMPT activators,resulting in the discovery of non-pyridyl class NAMPT activators

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Acta Pharmaceutica Sinica B 2023年第2期13卷 709-721页

作者： Siyuan Tang Miguel Garzon Sanz oliver smith Andreas Krämer Daniel Egbase Paul W.Caton Stefan Knapp Sam Butterworth Division of Pharmacy and Optometry School of Health SciencesManchester Academic Health Sciences CentreUniversity of ManchesterManchester M139PLUK Structural Genomics Consortium(SGC) 60438 Frankfurt Am MainGermany Buchmann Institute for Life Sciences(BMLS) 60438 Frankfurt Am MainGermany Institut für Pharmazeutische Chemie Goethe University60438 Frankfurt Am MainGermany Frankfurt Cancer Institute(FCI) 60596 Frankfurt Am MainGermany Department of Diabetes School of Cardiovascular and Metabolic Medicine&SciencesFaculty of Life Sciences&MedicineKing's College LondonLondon SE11ULUK

The cofactor nicotinamide adenine dinucleotide(NAD+)plays a key role in a wide range of physiological processes and maintaining or enhancing NAD+levels is an established approach to enhancing healthy ***,several classes of nicotinamide phosphoribosyl transferase(NAMPT)activators have been shown to increase NAD+levels in vitro and in vivo and to demonstrate beneficial effects in animal *** best validated of these compounds are structurally related to known urea-type NAMPT inhibitors,however the basis for the switch from inhibitory activity to activation is not well *** we report an evaluation of the structure activity relationships of NAMPT activators by designing,synthesising and testing compounds from other NAMPT ligand chemotypes and mimetics of putative phosphoribosylated adducts of known *** results of these studies led us to hypothesise that these activators act via a through-water interaction in the NAMPT active site,resulting in the design of the first known urea-class NAMPT activator that does not utilise a pyridine-like warhead,which shows similar or greater activity as a NAMPT activator in biochemical and cellular assays relative to known analogues.

关键词： Nicotinamide phosphoribosyl transferase activator Healthy aging Drug discovery Bioisosteres Medicinal chemistry

Pharmacological pain management in chronic pancreatitis

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World Journal of Gastroenterology 2013年第42期19卷 7292-7301页

作者： Sφren S Olesen Jacob Juel Carina Graversen Yuri Kolesnikov oliver HG Wilder-smith Asbjφrn M Drewes MechSense Department of Gastroenterology and HepatologyAalborg University Hospital9000 AalborgDenmark Mech-Sense Department of RadiologyAalborg University Hospital9000 AalborgDenmark Department of Neurorehabilitation Engineering Bernstein Center for Computational NeuroscienceUniversity Medical Center G ttingenGeorg-August UniversityD-37077 GttingenGermany Pain Service Department of OncologyEast Tallinn Central Hospital19086 TallinnEstonia Pain and Nociception Neuroscience Research Group Department of AnaesthesiologyPain and Palliative CareRadboud University Nijmegen Medical Centre6525 NijmegenThe Netherlands Center for Sensory-Motor Interaction Department of Health Science and TechnologyAalborg University9000 AalborgDenmark

Intense abdominal pain is a prominent feature of chronic pancreatitis and its treatment remains a major clinical *** studies of pancreatic nerves and experimental human pain research have provided evidence that pain processing is abnormal in these patients and in many cases resembles that seen in neuropathic and chronic pain *** important ultimate outcome of such aberrant pain processing is that once the disease has advanced and the pathophysiological processes are firmly established,the generation of pain can become self-perpetuating and independent of the initial peripheral nociceptive ***,the management of pain by traditional methods based on nociceptive deafferentation(e.g.,surgery and visceral nerve blockade)becomes difficult and often *** novel and improved understanding of pain aetiology requires a paradigm shift in pain management of chronic *** mechanism based pain treatments taking into account altered pain processing are likely to increasingly replace invasive therapies targeting the nociceptive source,which should be reserved for special and carefully selected *** this review,we offer an overview of the current available pharmacological options for pain management in chronic *** addition,future options for pain management are discussed with special emphasis on personalized pain medicine and multidisciplinarity.

关键词： Chronic pancreatitis Pain Treatment Pharmacology Analgesics Adjuvant analgesics

E-technology social support programs for autistic children: Can they work?

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World Journal of Psychiatry 2021年第12期11卷 1239-1246页

作者： Natalie G Wall oliver smith Linda E Campbell Carmel Loughland Mark Wallis Frans Henskens Ulrich Schall Centre for Brain and Mental Health Research The University of NewcastleCallaghan 2308NSWAustralia The Brain and Mental Health Research Program Hunter Medical Research InstituteNew Lambton Heights 2305NSWAustralia School of Psychology The University of NewcastleCallaghan 2308NSWAustralia

Autism is a neurodevelopmental condition with associated difficulties that present differently across *** such difficulty is recognizing basic and complex facial *** has previously found that there are many evidence-based support programs available for building non-verbal communication *** programs are frequently administered with a therapist or in a group setting,making them inflexible in *** hosted on e-technology are becoming increasingly popular,with many parents supportive of ***(apps)that are hosted on technology such as iPads or mobile phones allow users to engage in building skills in real-time social settings and own what they are *** technologies are frequently used by autistic children,with apps typically focusing on identifying facial *** at this current time,there are mixed reviews of how to design such programs and what their theoretical backing is,with many studies using a mix of observation and psychological assessments as outcome ***-tracking and electroencephalography are established methodologies that measure neural processing and gaze behaviors while viewing *** better support the field moving forward,objective measures such as these are a way to measure outcomes of apps that are designed for helping children on the spectrum build skills in understanding facial expressions.

关键词： Autism Facial expression recognition Technology Eye-tracking Electroen-cephalography

Sensory testing of the human gastrointestinal tract

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World Journal of Gastroenterology 2009年第2期15卷 151-159页

作者： Christina Brock Lars Arendt-Nielsen oliver Wilder-smith Asbjφrn Mohr Drewes Mech-Sense Department of Gastroenterology Aalborg Hospital DK-9000 Aalborg Denmark Center for Sensory-Motor Interactions Department of Health Science and Technology Aalborg University DK-9000 Aalborg Denmark Pain and Nociception Research Group Department of Anaesthesiology Radboud University Nijmegen Medical Centrethe Netherlands Mech-Sense Department of Gastro-enterology Aalborg Hospital DK-9000 Aalborg Denmark Author

The objective of this appraisal is to shed light on the various approaches to screen sensory information in the human gut. Understanding and characterization of sensory symptoms in gastrointestinal disorders is poor. Experimental methods allowing the investigator to control stimulus intensity and modality, as well as using validated methods for assessing sensory response have contributed to the understanding of pain mechanisms. Mechanical stimulation based on impedance planimetry allows direct recordings of luminal cross-sectional areas, and combined with ultrasound and magnetic resonance imaging, the contribution of different gut layers can be estimated. Electrical stimulation depolarizes free nerve endings non-selectively. Consequently, the stimulation paradigm （single, train, tetanic） influences the involved sensory nerves. Visual controlled electrical stimulation combines the probes with an endoscopic approach, which allows the investigator to inspect and obtain small biopsies from the stimulation site. Thermal stimulation （cold or warm） activates selectively mucosal receptors, and chemical substances such as acid and capsaicin （either alone or in combination） are used to evoke pain and sensitization. The possibility of multimodal （e.g. mechanical, electrical, thermal and chemical） stimulation in different gut segments has developed visceral pain research. The major advantage is involvement of distinctive receptors, various sensory nerves and different pain pathways mimicking clinical pain that favors investigation of central pain mechanisms involved in allodynia, hyperalgesia and referred pain. As impairment of descending control mechanisms partly underlies the pathogenesis in chronic pain, a cold pressor test that indirectly stimulates such control mechanisms can be added. Hence, the methods undoubtedly represent a major step forward in the future characterization and treatment of patients with various diseases of the gut, which provides knowledge to dinicians

关键词： Endoscopy Intestine Experimental Neurophysiology Pain

Systematic mechanism-orientated approach to chronic pancreatitis pain

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World Journal of Gastroenterology 2015年第1期21卷 47-59页

作者： Stefan AW Bouwense Marjan de Vries Luuk TW Schreuder Soren S Olesen Jens B Frokjær Asbjorn M Drewes Harry van Goor oliver HG Wilder-smith Pain and Nociception Neuroscience Research Group Department of SurgeryRadboud University Medical Center6500HB GelderlandThe Netherlands Department of Gastroenterology and Hepatology and Clinical Medicine Aalborg University Hospital9100 AalborgDenmark Center for Sensory-Motor Interaction Department of Health Science and TechnologyAalborg University9100 AalborgDenmark Department of Anaesthesiology Pain and Palliative MedicineRadboud University Medical Center6500HB GelderlandThe Netherlands

Pain in chronic pancreatitis(CP) shows similarities with other visceral pain syndromes(i.e.,inflammatory bowel disease and esophagitis),which should thus be managed in a similar *** causes of CP pain include increased intrapancreatic pressure,pancreatic inflammation and pancreatic/extrapancreatic ***,CP pain continues to be a major clinical *** is recognized that ongoing pain may induce altered central pain processing,e.g.,central sensitization or pro-nociceptive pain *** this is present conventional pain treatment targeting the nociceptive focus,e.g.,opioid analgesia or surgical/endoscopic intervention,often fails even if technically *** central nervous system pain processing is altered,specific treatment targeting these changes should be instituted(e.g.,gabapentinoids,ketamine or tricyclic antidepressants).Suitable tools are now available to make altered central processing visible,including quantitative sensory testing,electroencephalograpy and(functional) magnetic resonance *** techniques are potentially clinically useful diagnostic tools to analyze central pain processing and thus define optimum management approaches for pain in CP and other visceral pain *** present review proposes a systematic mechanism-orientated approach to pain management in CP based on a holistic view of the mechanisms *** research should address the circumstances under which central nervous system pain processing changes in CP,and how this is influenced by ongoing nociceptive input and *** we hope to predict which patients are at risk for developing chronic pain or not responding to therapy,leading to improved treatment of chronic pain in CP and other visceral pain disorders.

关键词： Chronic pancreatitis Pain Pain treatment Central sensitization Quantitative sensory testing Electroencephalograpy Magnetic resonance imaging

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人类学与灾难研究的范式

云南民族大学学报（哲学社会科学版） 2014年第1期31卷 30-35页

作者：苏珊娜·M·霍夫曼安东尼·奥利弗-斯密斯彭文斌(编译) 旧金山大学人类学系佛罗里达大学人类学系

近年来,人类学在理论和方法上对灾难的研究越来越重视。人类学作为社会科学将灾难中交汇的环境、生物和社会文化三个因素纳入思考的范畴,并在研究中形成了"考古与历史"、"政治生态学"、"社会文化与行为"和"应用与实践"几种范式。这些范... 详细信息

近年来,人类学在理论和方法上对灾难的研究越来越重视。人类学作为社会科学将灾难中交汇的环境、生物和社会文化三个因素纳入思考的范畴,并在研究中形成了"考古与历史"、"政治生态学"、"社会文化与行为"和"应用与实践"几种范式。这些范式之间相互关联,吸取了其他学科的灾难研究经验,以人类学整体观的视野和微观的民族志田野方法对灾难研究作出了独特的贡献。

关键词：人类学灾难研究范式与实践

王者归来？探索利用基因组编辑技术复活灭绝物种存在的局限性

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王者归来？探索利用基因组编辑技术复活灭绝物种存在的局限性

Energy shift： decline of easy oil and restructuring of eo-politics

第十六届全国野生动物生态与资源保护学术研讨会

作者：林剑青 David Duchêne Christian Car?e oliver smith Marta Maria Ciucani Jonas Niemann Douglas Richmond Alex D.Greenwood Ross MacPhee 张国捷 Shyam Gopalakrishnan M.Thomas P.Gilbert Guangdong Provincial Key Laboratory of Marine Biotechnology Institute of Marine Science Shantou University MOE Key Laboratory of Biosystems Homeostasis & Protection State Conservation Centre for Gene Resources of Endangered Wildlife College of Life Sciences Zhejiang University Center for Evolutionary Hologenomics the GLOBE Institute University of Copenhagen Section for Evolutionary Genomics the GLOBE Institute University of Copenhagen Mammalogy/Vertebrate Zoology & AMNH Gilder Graduate School American Museum of Natural History China National Genebank BGI-Shenzhen Villum Center for Biodiversity Genomics Section for Ecology and Evolution Department of Biology University of Copenhagen State Key Laboratory of Genetic Resources and Evolution Kunming Institute of Zoology Chinese Academy of Sciences Center for Excellence in Animal Evolution and Genetics Chinese Academy of Sciences Bioinformatics Department of Health Technology Technical University of Denmark Norwegian University of Science and Technology (NTNU) University Museum

物种复活(De-extinction,也称"反灭绝")是受到广泛关注和讨论的热门话题。当前,有三种手段可实现灭绝物种"复活":(1)反向繁育;(2)通过跨物种体细胞核移植进行克隆;(3)利用基因编辑技术对近缘物种进行编辑,以获得尽可能接近灭绝物种的基... 详细信息

物种复活(De-extinction,也称"反灭绝")是受到广泛关注和讨论的热门话题。当前,有三种手段可实现灭绝物种"复活":(1)反向繁育;(2)通过跨物种体细胞核移植进行克隆;(3)利用基因编辑技术对近缘物种进行编辑,以获得尽可能接近灭绝物种的基因组。其中,第三种手段可以适用的物种最多,但其最终应用潜力取决于灭绝物种的基因组能在多大程度上被重建。我们提取了由牛津大学自然历史博物馆提供的两个圣诞岛大鼠标本的皮肤DNA,并进行基因组测序,将测序数据比对到挪威褐鼠(Norway brown rat,Rattus norvegicus)参考基因组上,结果发现,虽然测序平均深度高达60.81×,却仅能覆盖到挪威褐鼠基因组95.15%的区域。我们构建了5个大鼠物种的系统进化树并确定物种间分化的时间。虽然这5个物种在230万年前才由共同祖先分化,但这一进化分歧已经足以明显降低其基因组测序数据比对到挪威褐鼠的基因组的覆盖度,其中亚洲家鼠已经低至92.76%。圣诞岛大鼠测序数据无法覆盖的位点有四分之一位于挪威褐鼠的基因区域,其中,有1661个基因的覆盖度低于90%,甚至有26个基因完全无法被测序数据覆盖到。因此,缺失这些序列信息可能会产生功能性的影响。挪威褐鼠基因上不被完全覆盖的基因并不是在基因组上随机分布的。对覆盖度低于90%的基因进行功能分析发现,他们在免疫应答和嗅觉功能有关的类别中显著富集。当前的物种复活工作聚焦在猛犸象和旅鸽等物种,不太可能会有人想尝试复活一只大鼠。尽管如此,我们基于对这一对亲缘关系很近的大鼠物种的分析说明,当灭绝和现存物种的进化分歧增大的时候,所带来的挑战会更大。在这样的背景下,我们注意到,猛犸象和亚洲象的基因组分化程度与圣诞岛大鼠和挪威褐鼠基因组分化程度是相近的,而旅鸽和斑尾鸽之间的距离更大(2.24倍)。由于分化距离不仅跟物种分化的绝对时间有关,也跟世代时间有关,每个物种复活项目启动之前,最好能逐个进行分析论证。该论文展示的方法,可以为未来"物种复活"项目提供一个可行性论证框架。

关键词：物种复活进化分歧古DNA 圣诞岛大鼠分子定年

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Frontiers in Energy 2016年第3期10卷 260-267页

作者： oliver R. INDERWILDI David A. KING smith School of Enterprise and the Environment University of OxfordOxford OX1 3QY United Kingdom

This paper critically assesses the geopolitical and geo-economic impact of novel fuel resources on both resource exporters and importers. Presently, very strong political and economic forces drive the utilisation of domestic, unconventional oil and gas recovery in the West as these enhance energy security and ease balance of payment issues. The additional capacity generated by this trend has, supported by other effects such as Saudi Arabia＇s decision to maintain current production, triggered a significant reduction ofoil prices. Consequently, it is now oil exporters that struggle with the balance of payment issues and often these countries base their fiscal budget completely on fossil fuel revenues. In fact, these unconventional resources help turn the tide while oil exporters are now politically significantly weakened due to the increased energy sufficiency of the West. The catch is that the extraction of unconventional types ofoil has many environmental implications. So, internalising the environ- mental externalities have to be considered. This paper, therefore, assesses, next to geopolitics and geo-economics, the environmental implications of this trend.

关键词： energy security climatic change geo-economics geopolitics unconventional resources macroeconomics

Macroeconomic impacts of oil price volatility： mitigation and resilience

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Frontiers in Energy 2014年第1期8卷 9-24页

作者： Zoheir EBRAHIM oliver R, INDERWILDI David A. KING smith School of Enterprise and the Environment University of OxfordOxford OX1 3QY United Kingdom

Dependency sectors, most notably on oil-derived fuels in various in mobility, has left the global economy vulnerable to several macroeconomic economic side effects. Numerous studies have addressed the effect of price volatility on specific economic parameters. However, the current literature lacks a comprehensive review of the interactions between global macroeconomic performance and oil price volatility （OPV）. Price volatility is intrinsic in commodity markets, but has been advancing at a faster rate in the crude oil market in comparison to other commodities over the past decade, reflecting the status ofoil as the most globalised commodity. In this paper, the analytical literature review and analysis of the behavioral responses of macroeconomic agents to OPV shows that such volatility has several damaging and destabilizing macro- economic impacts that will present a fundamental barrier to future sustainable economic growth if left unchecked. To ensure macroeconomic isolation from OPV, a combination of supply and demand-side policies have been recom- mended that can help to mitigate and build resilience to the economic uncertainty advanced by OPV.

关键词： conventional oil price volatility macroecon-omy economic stability energy security