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Combining Human and Rodent Genetics to Identify New Analgesics

Neuroscience Bulletin 2018年第1期34卷 143-155页

作者： Alban Latremoliere michael Costigan Kirby Neurobiology Center Boston Children's Hospital and Department of Neurobiology Harvard Medical School Department of Anesthesiology Perioperative and Pain Medicine Boston Children's Hospital

Most attempts at rational development of new analgesics have failed, in part because chronic pain involves multiple processes that remain poorly understood. To improve translational success, one strategy is to select novel targets for which there is proof of clinical relevance, either genetically through heritable traits, or pharmacolog- ically. Such an approach by definition yields targets with high clinical validity. The biology of these targets can be elucidated in animal models before returning to the patients with a refined therapeutic. For optimal treatment, having biomarkers of drug action available is also a plus. Here we describe a case study in rational drug design： the use of controlled inhibition of peripheral tetrahydrobiopterin （BH4） synthesis to reduce abnormal chronic pain states without altering nociceptive-protective pain. Initially iden- tified in a population of patients with low back pain, the association between BH4 production and chronic pain has been confirmed in more than 12 independent cohorts, through a common haplotype （present in 25% of Cau- casians） of the rate-limiting enzyme for BH4 synthesis, GTP cyclohydrolase 1 （GCH1）. Genetic tools in mice have demonstrated that both injured sensory neurons and activated macrophages engage increased BH4 synthesis to cause chronic pain. GCH1 is an obligate enzyme for de novo BH4 production. Therefore, inhibiting GCH1 activity eliminates all BH4 production, affecting the synthesis of multiple neurotransmitters and signaling molecules and interfering with physiological function. In contrast, target- ing the last enzyme of the BH4 synthesis pathway, sepiapterin reductase （SPR）, allows reduction of patholog- ical BH4 production without completely blocking physio- logical BH4 synthesis. Systemic SPR inhibition in mice has not revealed any safety concerns to date, and available genetic and pharmacologic data suggest similar responses in humans. Finally, because it is present in vivo only when SPR is inhi

关键词： Chronic pain Genetics Mouse models Tetrahydrobiopterin Sepiapterin reductase Analgesics

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On the critical behavior of a homopolymer model

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Science China Mathematics 2019年第8期62卷 1463-1476页

作者： michael Cranston Stanislav Molchanov Department of Mathematics University of California at Irvine Irvine CA 92697-3875 USA Department of Mathematics The University of North Carolina Charlotte NC 28223 USA

We begin with the reference measure P0 induced by simple, symmetric nearest neighbor continuous time random walk on Zd starting at 0 with jump rate 2d and then define, for β≥0, t > 0, the Gibbs probability measure Pβ,t by specifying its density with respect to P0 as dPβ,t/dP0= Zβ,t（0）(-1eβ∫0tδ0（xs）ds),（0.1）where Zβ,t（0）≡E0[eβ∫t0δ0（xs）ds]. This Gibbs probability measure provides a simple model for a homopolymer with an attractive potential at the origin. In a previous paper（Cranston and Molchanov, 2007）, we showed that for dimensions d≥3 there is a phase transition in the behavior of these paths from the diffusive behavior for β below a critical parameter to the positive recurrent behavior for β above this critical value. The critical value was determined by means of the spectral properties of the operator ? + βδ0, where ? is the discrete Laplacian on Zd. This corresponds to a transition from a diffusive or stretched-out phase to a globular phase for the polymer. In this paper we give a description of the polymer at the critical value where the phase transition takes place. The behavior at the critical parameter is dimension-dependent.

关键词： Gibbs measure homopolymer phase transition globular phase diffusive phase

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FINITE ELEMENT EXTERIOR CALCULUS FOR PARABOLIC EVOLUTION PROBLEMS ON RIEMANNIAN HYPERSURFACES

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Journal of Computational Mathematics 2018年第6期36卷 792-832页

作者： michael Hoist Christopher Tiee Department of Mathematics University of California San Diego La Jolla CA 92093 USA

Over the last ten years, Finite Element Exterior Calculus （FEEC） has been developed as a general framework for linear mixed variational problems, their numerical approximation by mixed methods, and their error analysis. The basic approach in FEEC, pioneered by Arnold, Falk, and Winther in two seminal articles in 2006 and 2010, interprets these problems in the setting of Hilbert complexes, leading to a more general and complete understanding. Over the last five years, the FEEC framework has been extended to a broader set of problems. One such extension, due to Hoist and Stern in 2012, was to problems with variational crimes, allowing for the analysis and numerical approximation of linear and geometric elliptic partial differential equations oil Riemannian manifolds of arbitrary spatial dimension. Their results substantially generalize the existing surface finite element approximation theory in several respects. In 2014, Gillette, Hoist, and Zhu extended FEEC in another direction, namely to parabolic and hyperbolic evolution systems by combining the FEEC framework for elliptic operators with classical approaches for parabolic and hyperbolic operators, by viewing solutions to the evolution problem as lying in Bochner spaces （spaces of Banach-space valued parametrized curves）. Related work on developing an FEEC theory for parabolic evolution problems has also been done independently by Arnold and Chen. In this article, we extend the work of Gillette-Holst- Zhu and Arnold-Chen to evolution problems on Riemannian manifolds, through tile use of framework developed by Holst and Stern for analyzing variational crimes. We establish a priori error estimates that reduce to the results from earlier work in tile flat （non-criminal） setting. Some numerical examples are also presented.

关键词： FEEC Elliptic equations Evolution equations Approximation theory Inf-supconditions A priori estimates Variational crimes Equations on manifolds

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The insect cellular immune response

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Insect Science 2008年第1期15卷 1-14页

作者： michael R. Strand Department of Entomology and Center for Emerging and Tropical Global Diseases University of Georgia Athens Georgia USA

The innate immune system of insects is divided into humoral defenses that include the production of soluble effector molecules and cellular defenses like phagocytosis and encapsulation that are mediated by hemocytes. This review summarizes current understand- ing of the cellular immune response. Insects produce several terminally differentiated types of hemocytes that are distinguished by morphology, molecular and antigenic markers, and function. The differentiated hemocytes that circulate in larval or nymphal stage insects arise from two sources： progenitor cells produced during embryogenesis and mesodermally derived hematopoietic organs. Regulation of hematopoiesis and hemocyte differentiation also involves several different signaling pathways. Phagocytosis and encapsulation require that hemocytes first recognize a given target as foreign followed by activation of downstream signaling and effector responses. A number of humoral and cellular receptors have been identified that recognize different microbes and multicellular parasites. In turn, activation of these receptors stimulates a number of signaling pathways that regulate different hemocyte functions. Recent studies also identify hemocytes as important sources Of a number of humoral effector molecules required for killing different foreign invaders.

关键词： antimicrobial peptides clotting cytokines Diptera Drosophila encapsulation,hemocytes immunity insects Lepidoptera nodulation phagocytosis

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Challenges and perspectives for structural biology of IncRNAs-the example of the Xist IncRNA A-repeats

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Journal of Molecular Cell Biology 2019年第10期11卷 845-859页

作者： Alisha NJones michael Sattler Institute of Structural Biology Helmholtz Zentrum MunchenNeuherberg85764Germany Center for Integrated Protein Scienee Munich and Bavarian NMR Center at Department of Chemistry Technical University of MunichGarching85747Germany

Following the discovery of numerous long non-coding RNA(IncRNA)transcripts in the human genome,their important roles in biology and human disease are *** progress in experimental methods has enabled the identification of structural features of ***,determining high-resolution structures is challenging as IncRNAs are expected to be dynamic and adopt multiple conformations,which may be modulated by interaction with protein binding *** X-inactive specific transcript(Xist)is necessary for X inactivation during dosage compensation in female placental mammals and one of the beststudied *** progress has provided new insights into the domain organization,molecular features,and RNA binding proteins that interact with distinct regions of *** A-repeats located at the 5'end of the transcript are of particular interest as they are essential for mediating silencing ofthe inactive X ***,we discuss recent progress with elucidating structural features of the Xist IncRNA,focusing on the *** discuss the experimental and computational approaches employed that have led to distinct structural models,likely reflecting the intrinsic dynamics of this *** presence of multiple dynamic conformations may also play an important role in the formation ofthe associated RNPs,thus influencing the molecular mechanism underlying the biological function of the Xist *** propose that integrative approaches that combine biochemical experiments and high-resolution structural biology in vitro with chemical probing and functional studies in vivo are required to unravel the molecular mechanisms of IncRNAs.

关键词： In cRNA structural biology Xist chemical pro bing enzymatic footpri nting computational structure predicti on

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OPTIMAL CONTROL OF THE LAPLACE-BELTRAMI OPERATOR ON COMPACT SURFACES： CONCEPT AND NUMERICAL TREATMENT

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Journal of Computational Mathematics 2012年第4期30卷 392-403页

作者： michael Hinze Morten Vierling Schwerpunkt Optimierung und Approximation Universit~it Hamburg Bundesstrafle 55 20146 Hamburg Germany

We consider optimal control problems of elliptic PDEs on hypersurfaces F in R^n for n = 2, 3. The leading part of the PDE is given by the Laplace-Beltrami operator, which is discretized by finite elements on a polyhedral approximation of F. The discrete optimal control problem is formulated on the approximating surface and is solved numerically with a semi-smooth Newton algorithm. We derive optimal a priori error estimates for problems including control constraints and provide numerical examples confirming our analytical findings.

关键词： Elliptic optimal control problem Laplace-Beltrami operator Surfaces Controlconstraints Error estimates Semi-smooth Newton method.

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Neuronal trafficking as a key to functional recovery in immune-mediated neuropathies

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Neural Regeneration Research 2024年第11期19卷 2331-2332页

作者： Felix Kohle michael Schroeter Department of Neurology University of Cologne and University Hospital CologneCologneGermany

Immune-mediated neuropathies are rare diseases of the peripheral nervous system(PNS),substantially affecting patients’functionality and quality of *** are amenable to immunomodulatory treatments,which in many cases stabilize disease progression,but long-term deficits persist in many *** long-term deficits are particularly observed in monophasic autoimmune neuropathies like Guillain-Barrésyndrome and also in chronic variants,e.g.,chronic inflammatory demyelinating neuropathy(Fadia et al.,2019).

关键词： diseases autoimmune

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A river(of liquid metal) runs through it

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National Science Review 2020年第4期7卷 721-722页

作者： michael D. Dickey Department of Chemical and Biomolecular Engineering North Carolina State University

Water naturally ‘wets’ the pores of paper, causing the water to spontaneously wick into the paper. However, liquids do not wick into all porous materials. For example, pores in raincoats let heat pass from your body to the surroundings, yet water does not penetrate into the *** extent to which liquids pass through pores depends on their contact angle with the material(water on a waxed car has a high contact angle) and the surface tension of the liquid. Water, which has a large surface tension, will only pass through pores that it wets. Liquid metals have surface tensions that are nearly an order

关键词： of liquid metal A river runs through it

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Exosome treatment for stroke with diabetic comorbidity

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Neural Regeneration Research 2022年第2期17卷 315-317页

作者： Poornima Venkat michael Chopp Department of Neurology Henry Ford HospitalDetroitMIUSA Department of Physics Oakland UniversityRochesterMIUSA

Ischemic stroke is a cerebrovasculardisease with a high risk of mortality andlong-lasting neurological *** advances have resulted in adeclining trend in stroke incidence anddeaths in the United States. However,increas... 详细信息

关键词： mortality morbidity Exosome

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Modulation of ice ages via precession and dust-albedo feedbacks

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Geoscience Frontiers 2016年第6期7卷 891-909页

作者： Ralph Ellis michael Palmer 105-6817 Route Pommier St Martin Bellevue 74370France University of Waterloo Department of ChemistryWaterlooOntarioCanada

We present here a simple and novel proposal for the modulation and rhythm of ice-ages and interglacials during the late Pleistocene. While the standard Milankovitch-precession theory fails to explain the long intervals between interglacials, these can be accounted for by a novel forcing and feedback system involving CO2, dust and albedo. During the glacial period, the high albedo of the northern ice sheets drives down global temperatures and CO2 concentrations, despite subsequent precessional forcing maxima. Over the following millennia more CO2 is sequestered in the oceans and atmospheric concentrations eventually reach a critical minima of about 200 ppm, which combined with arid conditions, causes a die-back of temperate and boreal forests and grasslands, especially at high altitude. The ensuing soil erosion generates dust storms, resulting in increased dust deposition and lower albedo on the northern ice sheets. As northern hemisphere insolation increases during the next Milankovitch cycle, the dust-laden ice-sheets absorb considerably more insolation and undergo rapid melting, which forces the climate into an interglacial period. The proposed mechanism is simple, robust, and comprehensive in its scope, and its key elements are well supported by empirical evidence.

关键词： Paleoclimatology Ice-age Precession CO2 Albedo Dust

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