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Therapies for Tau-associated neurodegenerative disorders:targeting molecules,synapses,and cells

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Neural Regeneration Research 2023年第12期18卷 2633-2637页

作者： Miranda robbins MRC Laboratory of Molecular Biology Cambridge Biomedical CampusFrancis Crick AveTrumpingtonCambridgeUKUniversity of CambridgeDepartment of ZoologyCambridgeUK

Advances in experimental and computational technologies continue to grow rapidly to provide novel avenues for the treatment of neurodegenerative disorders. Despite this, there remain only a handful of drugs that have shown success in late-stage clinical trials for Tau-associated neurodegenerative disorders. The most commonly prescribed treatments are symptomatic treatments such as cholinesterase inhibitors and N-methyl-D-aspartate receptor blockers that were approved for use in Alzheimer's disease. As diagnostic screening can detect disorders at earlier time points, the field needs pre-symptomatic treatments that can prevent, or significantly delay the progression of these disorders(Koychev et al., 2019). These approaches may be different from late-stage treatments that may help to ameliorate symptoms and slow progression once symptoms have become more advanced should early diagnostic screening fail. This mini-review will highlight five key avenues of academic and industrial research for identifying therapeutic strategies to treat Tau-associated neurodegenerative disorders. These avenues include investigating(1) the broad class of chemicals termed “small molecules”;(2) adaptive immunity through both passive and active antibody treatments;(3) innate immunity with an emphasis on microglial modulation;(4) synaptic compartments with the view that Tau-associated neurodegenerative disorders are synaptopathies. Although this mini-review will focus on Alzheimer's disease due to its prevalence, it will also argue the need to target other tauopathies, as through understanding Alzheimer's disease as a Tau-associated neurodegenerative disorder, we may be able to generalize treatment options. For this reason, added detail linking back specifically to Tau protein as a direct therapeutic target will be added to each topic.

关键词： Alzheimer's disease antibody frontotemporal dementia immunotherapy small molecules synapses tau therapeutics

Synaptopathy in CHMP2B frontotemporal dementia highlights the synaptic vesicle cycle as a therapeutic target

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Neural Regeneration Research 2023年第2期18卷 315-316页

作者： Miranda robbins Emma L.Clayton MRC Laboratory of Molecular Biology Department of Zoology University of CambridgeCambridgeUK UK Dementia Research Institute at King’s College London Department of Basic and Clinical Neuroscience Institute of PsychiatryPsychology and NeuroscienceKing’s College LondonMaurice Wohl Clinical Neuroscience InstituteLondonUK

Amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD)are both devastating neurodegenerative *** affecting different regions of the nervous system(FTD affecting primarily the frontal and temporal lobes,whilst ALS presents with motor neuron loss),there is significant overlap between these conditions in terms of genetics,pathology,and disease mechanisms,and they are therefore often grouped as a spectrum of symptoms under the heading FTD/ALS(Abramzon et al.,2020).Significantly,there is currently no cure for ALS or ***,recent mechanistic insight points to a novel pathway to target for potential therapeutic intervention.

关键词： therapeutic pathology

Genomic insights into hybridization in a localized region of sympatry between pewee sister species(Contopus sordidulus × C. virens) and their chromosomal patterns of differentiation

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Chinese Birds 2016年第1期7卷 48-55页

作者： Joseph D.Manthey Mark B.robbins Biodiversity Institute University of Kansas Department of Ecology and Evolutionary Biology University of Kansas

Background: The Great Plains of the United States includes a large number of hybrid and contact zones between bird species. The amount of gene flow between sister species in these zones ranges from very rare hybridization events to widespread and prevalent introgression. Some of these avian systems have been studied extensively, while others have been indeterminate of whether hybridization exists in areas of sympatry. Using genomic-level approaches allows investigation of genomic patterns of hybridization and gene flow between species—or lack ***: We investigated a narrow zone of sympatry in Nebraska, USA between pewee species(Contopus sordidulus and C. virens), for which no hybridization has been confirmed. We used thousands of single nucleotide polymorphisms to identify potential hybridization and investigate genomic patterns of differentiation between these two ***: We found evidence of multiple hybrid individuals in the contact zone. Little genomic variation was fixed between species, but a large proportion had differentiated allele frequencies between species. There was a positive relationship between genetic differentiation and chromosome ***: We provided the first conclusive evidence of hybridization between C. sordidulus and C. virens, in a region where secondary contact likely occurred due to human disturbance and habitat modification. The genomic patterns of differentiation affirm that these species split in the relatively recent past. Finally, the relationship of chromosome size and genetic differentiation may have resulted from differential rates of chromosomal recombination in songbirds and genetic differentiation between species largely due to genetic drift(possibly in concert with selection).

关键词： Contact zone Hybrid zone Hybridization Chromosomal patterns Next-generation sequencing Contopus North America

TANGENT UNIT-VECTOR FIELDS:NONABELIAN HOMOTOPY INVARIANTS AND THE DIRICHLET ENERGY

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Acta Mathematica Scientia 2010年第5期30卷 1357-1399页

作者： A.Majumdar J.M.robbins M.Zyskin Mathematical Institute University of Oxford24-29 St.GilesOxford OX1 3LBUK School of Mathematics University of BristolUniversity WalkBristol BS8 1TWUK Department of Mathematics SETB 2.454-80 Fort BrownBrownsvilleTX 78520USA

Let O be a closed geodesic polygon in S2. Maps from O into S2 are said to satisfy tangent boundary conditions if the edges of O are mapped into the geodesics which contain them. Taking O to be an octant of S2, we compute the infimum Dirichlet energy 6（H） for continuous maps satisfying tangent boundary conditions of arbitrary homotopy type H. The expression for C（H） involves a topological invariant - the spelling length - associated with the （non-abelian） fundamental group of the n-times punctured two-sphere, π1（S2 - {s1,..., sn}, ＊）. The lower bound for C（H） is obtained from combinatorial group theory arguments, while the upper bound is obtained by constructing explicit representatives which, on all but an arbitrarily small subset of O, are alternatively locally conformal or anticonformal. For conformal and anticonformal classes （classes containing wholly conformal and anticonformal representatives respectively）, the expression for C（H） reduces to a previous result involving the degrees of a set of regular values sl,…… sn in the target 82 space. These degrees may be viewed as invariants associated with the abelianization of vr1（S2 - {s1,..., sn}, ＊）. For nonconformal classes, however, ε（H） may be strictly greater than the abelian bound. This stems from the fact that, for nonconformal maps, the number of preimages of certain regular values may necessarily be strictly greater than the absolute value of their degrees. This work is motivated by the theoretical modelling of nematic liquid crystals in confined polyhedral geometries. The results imply new lower and upper bounds for the Dirichlet energy （one-constant Oseen-Frank energy） of reflection-symmetric tangent unitvector fields in a rectangular prism.

关键词： harmonic maps conformal maps algebraic topology non-abelian homotopy invariants eombinatorics liquid crystals

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Membrane-based treatment of shale oil and gas wastewater:The current state of knowledge

作者： (美)Kay A. robbins (美)Steve robbins

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Frontiers of Environmental Science & Engineering 2019年第4期13卷 5-21页

作者： Tiezheng Tong Kenneth H. Carlson Cristian A. robbins Zuoyou Zhang Xuewei Du Department of Civil and Environmental Engineering Colorado State UniversityFort CollinsCO 80523USA

Shale oil and gas exploitation not only consumes substantial amounts of freshwater but also generates large quantities of hazardous wastewater. Tremendous research efforts have been invested in developing membrane-based technologies for the treatment of shale oil and gas wastewater. Despite their success at the laboratory scale, membrane processes have not been implemented at full scale in the oil and gas fields. In this article, we analyze the growing demands of wastewater treatment in shale oil and gas production, and then critically review the current stage of membrane technologies applied to the treatment of shale oil and gas wastewater. We focus on the unique niche of those technologies due to their advantages and limitations, and use mechanical vapor compression as the benchmark for comparison. We also highlight the importance of pretreatment as a key component of integrated treatment trains, in order to improve the performance of downstream membrane processes and water product quality. We emphasize the lack of sufficient efforts to scale up existing membrane technologies, and suggest that a stronger collaboration between academia and industry is of paramount importance to translate membrane technologies developed in the laboratory to the practical applications by the shale oil and gas industry.

关键词： Shale oil and gas production Wastewater treatment and reuse Membrane technology Pretreatment Academia-industry collaboration

A Continuum-Atomistic Multi-Timescale Algorithm for Micro/Nano Flows

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Communications in Computational Physics 2008年第10期4卷 1279-1291页

作者： Jin Liu Shiyi Chen Xiaobo Nie Mark O.robbins Department ofMechanical Engineering Johns Hopkins UniversityBaltimoreMD 21218USA State Key Laboratory for Turbulence and Complex Systems College of Engineering and Center for Computational Science and EngineeringPeking UniversityBeijingChina Department of Physics and Astronomy Johns Hopkins UniversityBaltimoreMD 21218USA Exa Corporation BurlingtonMA 01803USA

Amulti-timescale algorithmis proposed for simulating time-dependent problems in micro-and *** total simulation domain is spatially decomposed into two *** dynamics is employed in the crucial interfacial regions and continuum hydrodynamics is adopted in the remaining bulk *** coupling is through“constrained dynamics”in an overlap *** time scheme is based on the time scale separation between the continuum macro time step and molecular micro time *** allows the molecular dynamics during one macro time step to be treated as in quasi-steady ***,molecular simulation is only performed in two shorter time *** linear extrapolation of macroscopic velocities and re-initialization of particle configurations,we can significantly reduce the total computational *** demonstrate and discuss our time algorithm through hybrid simulation of channel flow driven by a sinusoidally moving top *** results are achieved for cases of large separation of time scale with much less computational cost than with the original hybrid simulation without time extrapolation.

关键词： Multi-scale simulation domain decompositions hybrid simulations micro-/nanofluidics

Repurposing an old anti-fungal drug as a Hedgehog inhibitor

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Protein & Cell 2010年第5期1卷 417-418页

作者： Camilla Giambelli Dennis Liang Fei Huaizhi Wang David J.robbins Molecular Oncology Program DeWitt Daughtry Family Department of SurgeryUniversity of MiamiMiamiFL 33136USA Department of Pharmacology and Toxicology Dartmouth Medical SchoolHanoverNH 03755USA Institute of Hepatopancreatobiliary Surgery of PLA Southwest HospitalThird Military Medical UniversityChongqing 400038China

It requires approximately 800 million dollars(US)and 10 years to successfully bring a drug from the laboratory bench into the clinic(DiMasi et al.,2003).Thus,the breakthrough discovery of today will not be available in the clinic for many years,and many dollars,after this initial *** potential way to speed up this drug developmental cycle is by repurposing drugs that have been previously approved for an alternate clinical *** this goal in mind,Beachy and colleagues set out to identify a drug with efficacy against tumors that were dependant on the Hedgehog(HH)signaling *** reported in the April issue of a leading cancer research journal that Itraconazole,a commonly used antifungal drug,can be turned against HH’s signaling function(Kim et al.,2010).It has been estimated that 25%of all human tumors may be HH dependent(Teglund et al,2010).

关键词： al. drugs dollar

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