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Crystal Structure of the MAP3K TAO2 Kinase Domain Bound by an Inhibitor Staurosporine

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Acta Biochimica et Biophysica Sinica 2006年第6期38卷 385-392页

作者： elizabeth J.GOLDSMITH USA TX 75390-9038 Department of Biochemistry University of Texas Southwestern Medical Center at Dallas

Mitogen-activated protein kinase (MAPK) signal transduction pathways are ubiquitous ineukaryotic cells,which transfer signals from the cell surface to the nucleus,controlling multiple *** are activated by MAPK kinases [MAP2Ks or MAP/extracellular signal-regulated kinase(ERK) kinases (MEK)],which in turn are activated by MAPK kinase kinases (MAP3Ks).TAO2 is a MAP3Klevel kinase that activates the MAP2Ks MEK3 and MEK6 to activate p38 *** p38 MAPKs arekey regulators of expression of inflammatory cytokines,they appear to be involved in human diseases suchas asthma and *** an upstream activator of p38s,TAO2 represents a potential drug *** we report the crystal structure of active TAO2 kinase domain in complex with staurosporine,a broad-range protein kinase inhibitor that inhibits TAO2 with an ICof 3 μ*** structure reveals that staurosporineoccupies the position where the adenosine of ATP binds in TAO2,and the binding of the inhibitor mimicsmany features of ATP *** polar and nonpolar interactions contribute to the *** induces conformational changes in TAO2 residues that surround the inhibitormolecule,but causes very limited global changes in the *** structure provides atomic details forTAO2-staurosporine interactions,and explains the relatively low potency of staurosporine against *** structure presented here should aid in the design of inhibitors specific to TAO2 and related kinases.

关键词： TAO2 MAP3K inhibitor staurosporine crystal structure

Sodium and water perturbations in patients who had an acute stroke:clinical relevance and management strategies for the neurologist

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Stroke & Vascular Neurology 2022年第3期7卷 258-266页

作者： Kevin C J Yuen Valerie Sharf elizabeth Smith Minhwan Kim Alissya S M Yuen Paul R MacDonald Departments of Neuroendocrinology and Neurosurgery Barrow Neurological InstitutePhoenixArizonaUSA University of Arizona College of Medicine and Creighton School of Medicine PhoenixArizonaUSA Department of Neurology Barrow Neurological InstitutePhoenixArizonaUSA Midwestern University GlendaleIllinoisUSA Creighton University School of Medicine PhoenixArizonaUSA University of California Davis DavisCaliforniaUSA

Sodium and water perturbations,manifesting as hyponatraemia and hypernatraemia,are common in patients who had an acute stroke,and are associated with worse outcomes and increased *** non-stroke related causes of sodium and water perturbations in these patients include underlying comorbidities and concomitant ***,hospitalised patients who had an acute stroke may receive excessive intravenous hypotonic solutions,have poor fluid intake due to impaired neurocognition and consciousness,may develop sepsis or are administered drugs(eg,mannitol);factors that can further alter serum sodium *** and water perturbations can also be exacerbated by the development of endocrine consequences after an acute stroke,including secondary adrenal insufficiency,syndrome of inappropriate antidiuretic hormone secretion and diabetes ***,COVID-19 infection has been reported to increase the risk of development of sodium and water perturbations that may further worsen the outcomes of patients who had an acute *** there are currently no accepted consensus guidelines on the management of sodium and water perturbations in patients who had an acute stroke,we conducted a systematic review of the literature published in English and in peer-reviewed journals between January 2000 and December 2020,according to PRISMA guidelines,to assess on the current knowledge and clinical practices of this *** this review,we discuss the signs and symptoms of hyponatraemia and hypernatraemia,the pathogenesis of hyponatraemia and hypernatraemia,their clinical relevance,and we provide our recommendations for effective treatment strategies for the neurologist in the management of sodium and water perturbations in commonly encountered aetiologies of patients who had an acute stroke.

关键词： patients impaired consequences

B cells in pancreatic cancer stroma

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World Journal of Gastroenterology 2022年第11期28卷 1088-1101页

作者： Francesca Romana Delvecchio Michelle R Goulart Rachel elizabeth Ann Fincham Michele Bombadieri Hemant M Kocher William Harvey Research Institute Queen Mary University of LondonLondon EC1M 6BQUnited Kingdom Barts Cancer Institute Queen Mary University of LondonLondon EC1M 6BQUnited Kingdom Barts and the London HPB Centre Barts Health NHS TrustLondon E11BBUnited Kingdom

Pancreatic cancer is a disease with high unmet clinical *** cancer is also characterised by an intense fibrotic stroma,which harbours many immune *** in both human and animal models have demonstrated that the immune system plays a crucial role in modulating tumour onset and *** human pancreatic ductal adenocarcinoma,high B-cell infiltration correlates with better patient ***,B cells have received recent interest in pancreatic cancer as potential therapeutic ***,the data on the role of B cells in murine models is unclear as it is dependent on the pancreatic cancer model used to ***,it appears that B cells do organise along with other immune cells such as a network of follicular dendritic cells(DCs),surrounded by T cells and DCs to form tertiary lymphoid structures(TLS).TLS are increasingly recognised as sites for antigen presentation,T-cell activation,Bcell maturation and differentiation in plasma *** this review we dissect the role of B cells and provide directions for future studies to harness the role of B cells in treatment of human pancreatic cancer.

关键词： B cells Pancreatic cancer Cancer immunology Tertiary lymphoid structures Anti-tumour immunoglobulins Plasma cells

Preoperative virtual video visits only:a convenient option that should be offered to caregivers beyond the pandemic

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World Journal of Pediatric Surgery 2022年第3期5卷 169-175页

作者： Danielle Dougherty Allison R Thompson Karen elizabeth Speck Erin E Perrone Section of Pediatric Surgery Department of SurgeryUniversity of Michigan Health SystemAnn ArborMichiganUSA Department of Health Behavior and Health Education University of Michigan School of Public HealthAnn ArborMIUSA

Objective During the COVID-19 pandemic,our group implemented preoperative video visits(VVs)to limit physical *** aim of this study was to determine caregivers’and providers’perceptions of this practice and to determine feasibility for *** All patients who had only a preoperative VV prior to an elective surgery were identified from March-October ***,surgeons,and clinic staff were surveyed about their *** Thirty-four preoperative VVs were followed by an elective surgery without a preceding in-person *** the 31 caregiver surveys completed,the majority strongly agreed that the VV was more convenient(87%,n=27).Eighty-one percent(n=25)strongly agreed or agreed that the VV saved them ***-four percent(n=29)strongly agreed or agreed that they would choose the VV option *** saved an average travel distance of 60.3 miles one way(range 6.1-480).Of the 13/17 providers who responded,77%(n=10)expressed that the practice should *** Virtual health became a necessity during the pandemic,and caregivers were overwhelmingly *** VVs as an option beyond the pandemic may be a reasonable and effective way to help eliminate some of the hurdles that impede healthcare-seeking behavior and should be offered.

关键词： convenient beyond eliminate

The Sendai Framework for Disaster Risk Reduction at Five:Lessons from the 2011 Great East Japan Earthquake and Tsunami

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International Journal of Disaster Risk Science 2020年第2期11卷 167-178页

作者： elizabeth Maly Anawat Suppasri International Research Institute of Disaster Science Tohoku UniversitySendai 980-8579.Japan

The Sendai Framework for Disaster Risk Reduction 2015–2030(SFDRR) represents an inclusive approach to disaster risk reduction, linked to development and recovery. Building on previous international guidelines, the SFDRR promotes practical and measurable outcomes for reducing disaster losses, including indicators to measure progress towards seven specific global *** in the context of the priorities and global targets of the SFDRR, the article considers the case of the Great East Japan Earthquake and Tsunami of 2011 to illustrate advances and limitations in pre-disaster tsunami hazard engineering and post-disaster recovery. With respect to the targets set out in the Sendai Framework related to risk reduction and tsunami engineering, especially Priority 1,understanding disaster risk, there have been significant advances in hazard assessment and systems for tsunami detection and warning. Although the SFDRR emphasizes actions in the recovery phase through Priority 4, enhancing disaster preparedness with an emphasis on the concept of build back better, on its own this does not function as a clear directive for guiding recovery. However, the overall people-centered and inclusive approach of the SFDRR, as well as the global targets and several sub-priorities, can be a useful way to shape good practices in recovery and evaluate recovery progress.

关键词： Build back better Disaster recovery Great East Japan Earthquake Sendai Framework Tsunami risk

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Distribution of Panama’s narrow-range trees:are there hot-spots?

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Forest Ecosystems 2021年第4期8卷 801-809页

作者： elizabeth Tokarz Richard Condit Morton Arboretum 4100 Illinois Rte.53LisleIL 60532USA

Background:Tree species with narrow ranges are a conservation concern because heightened extinction risk accompanies their small *** risks for these species is challenging,however,especially in tropical flora where their sparse populations seldom appear in traditional plots and ***,we utilize instead large scale databases that combine tree records from many sources to test whether the narrow-range tree species of Panama are concentrated at certain elevations or in certain *** investigations have suggested that the Choco region of eastern Panama and the high mountains of western Panama may be potential hotspots of narrow-range tree ***:All individual records were collected from public databases,and the range size of each tree species found in Panama was estimated as a polygon enclosing all its *** with ranges<20,000 km^(2) were defined as narrow *** divided Panama into geographic regions and elevation zones and counted the number of individual records and the species richness in each,separating narrow-range species from all other ***:The proportion of narrow endemics peaked at elevations above 2000 m,reaching 17.2% of the species *** elevation<1500 m across the country,the proportion was 6-11%,except in the dry Pacific region,where it was 1.5%.Wet forests of the Caribbean coast had 8.4% narrow-range species,slightly higher than other *** total number of narrow endemics,however,peaked at mid-elevation,not high elevation,because total species richness was highest at ***:High elevation forests of west Panama had higher proportions of narrow endemic trees than low-elevation regions,supporting their hot-spot status,while dry lowland forests had the lowest *** supports the notion that montane forests of Central America should be a conservation ***,given generally higher diversity at low-to mid-elevation,lowlands are also import

关键词： Narrow endemic trees Biodiversity hot-spots Panama Rarefaction High elevations BIEN database Narrow-range

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Adaptation to a novel host and performance trade-off in host-generalist and host-specific insect ectoparasites

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Insect Science 2022年第2期29卷 567-580页

作者： Irina S.Khokhlova Luther van der Mescht elizabeth M.Warburton Nadezhda A.Stavtseva Boris R.Krasnov Wyler Department of Dryland Agriculture French Associates Institute for Agriculture and Biotechnology of DrylandsJacob Blaustein Institutes for Desert ResearchBen-Gurion University of the NegevSede Boqer CampusMidreshet Ben-GurionIsrael Mitrani Department of Desert Ecology Swiss Institute for Dryland Environmental and Energy ResearchJacob Blaustein Institutes for Desert ResearchBen-Gurion University of the NegevSede Boqer CampusMidreshet Ben-GurionIsrael Clinvet International Center for the Ecology of Infectious Diseases Odum School of EcologyUniversity of Georgia

We investigated the performance trade-offs of fleas(Siphonaptera)while adapting to a novel host using two host generalists(Xenopsylla conformis and Xenopsylla ramesis)and one host specialist(Parapulex chephrenis)maintained on their principal hosts(Meriones crassus for Xenopsylla and Acomys cahirinus for ***).We asked whether,over generations,(i)a host generalist may become a specialist by evolving the ability to exploit a novel host and losing the ability to exploit an original host and(ii)a host specialist can become a generalist by evolving the ability to exploit a novel host without losing the ability to exploit an original *** established an experimental line of each species on a novel host(Acomys russatus for Xenopsylla and *** for ***)and maintained this line on this host during 23 *** compared reproductive performance of progenitors of each line and their descendants when they exploited either original or novel host in terms of egg number and size,hatching success,offspring production,and offspring *** found changes in performance over generations in female offspring size *** conformis demonstrated a tendency to become a host specialist(increased performance on the novel host with a concomitant decreased performance on the original host),whereas *** demonstrated a tendency to become a host generalist(increased performance on the novel host without a concomitant decreased performance on the original host).We conclude that the probability of generalist to specialist transition,and vice versa,is context-dependent and varies between species.

关键词： experimental evolution fleas generalist performance rodents specialist

A single measurement of fecal hemoglobin concentration outperforms polygenic risk score in colorectal cancer risk assessment

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Cancer Communications 2023年第8期43卷 947-950页

作者： Tobias Niedermaier elizabeth Alwers Xuechen Chen Thomas Heisser Michael Hoffmeister Hermann Brenner Division of Clinical Epidemiology and Aging Research German Cancer Research Center(DKFZ)HeidelbergBaden-WürttembergGermany Medical Faculty Heidelberg Heidelberg UniversityHeidelbergBaden-WürttembergGermany Division of Preventive Oncology German Cancer Research Center(DKFZ)HeidelbergBaden-WürttembergGermany German Cancer Consortium(DKTK) German Cancer Research Center(DKFZ)HeidelbergBaden-WürttembergGermany

Dear Editors,Large-scale genome-wide association studies have identified an increasing number of single nucleotide polymorphisms(SNPs)that are associated with colorectal cancer(CRC)risk[1].Polygenic risk scores(PRS)based on all established SNPs enable clinically relevant risk assessment that may help to develop novel risk-adapted prevention and screening strategies.

关键词： colorectal prevention cancer

Hepatic transcriptome profiling reveals early signatures associated with disease transition from non-alcoholic steatosis to steatohepatitis

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Liver Research 2022年第4期6卷 238-250页

作者： Nancy Magee Forkan Ahamed Natalie Eppler elizabeth Jones Priyanka Ghosh Lily He Yuxia Zhang Department of Pharmacology Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKSUSA Liver Center University of KansasKansas CityKSUSA

Background and aim:Non-alcoholic fatty liver disease(NAFLD)is becoming a leading cause of chronic liver disease *** molecular events that influence disease progression from non-alcoholic fatty liver(NAFL)to aggressive non-alcoholic steatohepatitis(NASH)remain incompletely understood,leading to lack of mechanism-based targeted treatment options for *** study aims to identify early signatures associated with disease progression from NAFL to NASH in mice and *** and methods:Male C57BL/6J mice were fed a high-fat,-cholesterol,and-fructose(HFCF)diet for up to 9 *** extent of steatosis,inflammation,and fibrosis was evaluated in liver *** RNA sequencing(RNA-seq)was conducted to determine liver transcriptomic ***:After being fed the HFCF diet,mice sequentially developed steatosis,early steatohepatitis,steatohepatitis with fibrosis,and eventually spontaneous liver *** RNA-seq revealed that the key signatures during steatosis progression to early steatohepatitis were pathways related to extracel-lular matrix organization and immune responses such as T cell migration,arginine biosynthesis,C-type lectin receptor signaling,and cytokine-cytokine receptor *** regulated by transcription factors forkhead box M1(FOXM1)and negative elongation factor complex member E(NELFE)were significantly altered during disease *** phenomenon was also observed in patients with NASH.

关键词： Liver Transcriptome Steatosis Inflammation Fibrosis Non-alcoholic steatohepatitis(NASH)