Parallelisation of greedy algorithms for compressive sensing reconstruction

Compressive Sensing (CS) is a technique which allows a signal to be compressed at the same time as it is captured. The process of capturing and simultaneously compressing the signal is represented as linear sampling, which can encompass a variety of physical processes or signal processing. Instead of explicitly identifying redundancies in the source signal, CS relies on the property of sparsity in order to reconstruct the compressed signal. While linear sampling is much less burdensome than conventional compression, this is more than made up for by the high computational cost of reconstructing a signal which has been captured using CS. Even when using some of the fastest reconstruction techniques, known as greedy pursuits, reconstruction of large problems can pose a significant burden, consuming a great deal of memory as well as compute time. Parallel computing is the foundation of the field of High Performance Computing (HPC). Modern supercomputers are generally composed of large clusters of standard servers, with a dedicated low-latency high-bandwidth interconnect network. On such a cluster, an appropriately written program can harness vast quantities of memory and computational power. However, in order to exploit a parallel compute resource, an algorithm usually has to be redesigned from the ground up. In this thesis I describe the development of parallel variants of two algorithms commonly used in CS reconstruction, Matching Pursuit (MP) and Orthogonal Matching Pursuit (OMP), resulting in the new distributed compute algorithms DistMP and DistOMP. I present the results from experiments showing how DistMP and DistOMP can utilise a compute cluster to solve CS problems much more quickly than a single computer could alone. Speed-up of as much as a factor of 76 is observed with DistMP when utilising 210 workers across 14 servers, compared to a single worker. Finally, I demonstrate how DistOMP can solve a problem with a 429GB equivalent sampling matrix in as little as 62 minutes using a 16-node compute cluster.Funded by an ICASE award from the Engineering and Physical Sciences Research Council, with sponsorship provided by Thales Research and Technology

Novel partners support two-way by-product mutualism in a converted ecosystem

Dissertação de Mestrado em Química Medicinal apresentada à Faculdade de Ciências e Tecnologia da Universidade de Coimbra.Nas sociedades modernas assiste-se a um aumento crescente do número de bactérias e vírus com resistência aos fármacos atualmente disponibilizados pela indústria farmacêutica. Dada a relevância da problemática mencionada, o objetivo central do trabalho apresentado nesta dissertação consiste no desenvolvimento de métodos de síntese de novas entidades químicas biocompatíveis constituídas por macrociclos tetrapirrólicos e sulfonamidas, tendo em vista a sua futura potencial aplicação dual como antibacteriano per si e como fotossensibilizador para inativação de bactérias recorrendo a terapia fotodinâmica. A combinação destas duas famílias de compostos pode ocorrer por ligação covalente ou via self-assembly, subdividindo o trabalho apresentado. No capítulo 1 apresenta-se uma revisão crítica e selecionada da literatura subjacente aos diferentes tópicos estudados. No capítulo 2 descreve-se uma estratégia de síntese de macrociclos tetrapirrólicos e sulfonamidas unidas por ligação covalente. Neste começa-se por selecionar a a 5,10,15,20-tetraquis(pentafluorofenil)porfirina como porfirina base para realizar os estudos de otimização da sua derivatização com a metanosulfonamida, conseguindo-se obter com sucesso condições de síntese seletivas para a formação da 5-[2’,3’,5’,6’-tetrafluoro-4’- metanosulfamoil)fenil]-10,15,20-tri-[(2’,3’,4’,5’,6’-pentafluoro)fenil]porfirina (composto monossubstituido) ou da 5,10,15,20-tetra-[2’,3’,5’,6’-tetrafluoro-4’-metanosulfamoil)fenil]porfirina (composto tetrassubstituído) com rendimentos de 19% e 70%, respetivamente. Com o intuito de avaliar o efeito da estrutura da sulfonamida na reatividade alargaram-se os estudos utilizando como nucleófilo duas sulfonamidas previamente sintetizadas no decorrer do trabalho: ptoluenosulfonamida e N-metil-p-toluenosulfonamida. Através deste estudo foi possível sintetizar e isolar os compostos mono e dissubstituídos da família da p-toluenosulfonamida (5-[(2’,3’,5’,6’- tetrafluoro-4’-p-toluenosulfamoil)fenil]-10,15,20-tri-[(2’,3’,4’,5’,6’-pentafluoro)fenil]porfirina e mistura de 5,10-[(2’,3’,5’,6’-tetrafluoro-4’-p-toluenosulfamoil)fenil]-15,20-dis-[(2’,3’,4’,5’,6’- pentafluoro)fenil]porfirina e 5,15-[(2’,3’,5’,6’-tetrafluoro-4’-p-toluenosulfamoil)fenil]-10,20- [(2’,3’,4’,5’,6’-pentafluoro)fenil]porfirina) e os compostos mono, di e trissubstituído referentes à substituição com a N-metil-p-toluenosulfonamida (5-[(2’,3’,5’,6’-tetrafluoro-4’-N-metil-ptoluenosulfamoil) fenil]-10,15,20-tri-[(2’,3’,4’,5’,6’-pentafluoro)fenil] porfirina, mistura de 5,10- [(2’,3’,5’,6’-tetrafluoro-4’-N-metil-p-toluenosulfamoil)fenil]-15,20-dis-[(2’,3’,4’,5’,6’- pentafluoro)fenil]porfirina e 5,15-[(2’,3’,5’,6’-tetrafluoro-4’-N-metil-p-toluenosulfamoil)fenil]-10,20- [(2’,3’,4’,5’,6’-pentafluoro)fenil]porfirina e 5,10,15-tri-[(2’,3’,5’,6’-tetrafluoro-4’-N-metil-ptoluenosulfamoil) fenil]-20-[(2’,3’,4’,5’,6’-pentafluoro)fenil]porfirina) com baixos rendimentos (0.6 a 4.5%). A título de exemplo, adotaram-se as condições otimizadas para a síntese da porfirina tetrassubstituída contendo a N-metil-p-toluenosulfonamida como substituinte, obtendo-se a correspondente 5,10,15,20-tetra-[(2’,3’,5’,6’-tetrafluoro-4’-N-metil-p-toluenosulfamoil)fenil] porfirina com um rendimento de 20%. Dado o nosso interesse no desenvolvimento de potenciais fotossensibilizadores com espectros de absorção na designada “janela terapêutica”., prosseguimos com estudos de redução de uma das porfirinas com hidrazina aquosa (NH2NH2·H2O) e cloreto de ferro(III)hexahidratado (FeCl3·6H2O), tendo-se obtido a correspondente 5,10,15,20-tetra- [2’,3’,5’,6’-tetrafluoro-4’-metanosulfamoil)fenil]clorina com rendimento de produto isolado elevado (65%). Para além disso com recurso ao método de redução de porfirinas com ptoluenosulfonilhidrazina sem solvente conseguiu-se obter a 5,10,15,20-tetra-[2’,3’,5’,6’-tetrafluoro- 4’-metanosulfamoil)fenil]bacterioclorina um rendimento de 70%. Os compostos foram caracterizados fotofísicamente, tendo revelado possuir características bastante promissoras para aplicação como fotossensibilizadores, tais como, baixos rendimentos quânticos de fluorescência (фF≤0.1375) e rendimentos quânticos de formação de oxigénio singleto adequados (фΔ≥0.59). Para avaliar a lipofilicidade e a interação com a membrana lipídica procedeuse ao cálculo do coeficiente de partição das porfirinas 5-[2’,3’,5’,6’-tetrafluoro-4’- metanosulfamoil)fenil]-10,15,20-tri-[(2’,3’,4’,5’,6’-pentafluoro)fenil]porfirina e 5,10,15,20-tetra- [2’,3’,5’,6’-tetrafluoro-4’-metanosulfamoil)fenil]porfirina através de duas metodologias, uma delas recorrendo à mistura octanol-água e a outra a vesículas unilamelares lipídicas (LUVs). Em suma, verificou-se que o número de derivatizações com grupos metanosulfonamida é crucial para modular a anfifilicidade dos compostos, sendo que estes apresentam variações significativas nos seus coeficientes de partição octanol-água (0.94≤LogP≤4). Apesar destes valores díspares, ambos apresentam uma elevada afinidade para as membranas lipídicas. Por fim, realizaram-se estudos preliminares de citotoxicidade no escuro, com a linha celular 3T3, demonstrando-se que o composto não apresenta toxicidade in vitro. No capítulo 3 desenvolve-se uma metodologia baseada no conceito de self-assembly, para a preparação de estruturas contendo porfirinas catiónicas descritas na inativação de bactérias [iodeto de 5,10,15,20-tetraquis(4-metilpiridil)porfirinato de zinco (II) e iodeto de 5,10,15,20-tetraquis(1,3- dimetilimidazol-2-il)porfirinato de zinco (II)] e a Sulfadiazina, uma sulfonamida com atividade bacteriostática comprovada. No capítulo 4 apresenta-se detalhadamente os procedimentos experimentais referentes a todos os capítulos da tese bem como a caracterização química completa de todas as moléculas sintetizadas no decorrer do trabalho (1H RMN, 19F RMN, espectrometria de massa e absorção UVVisModern society is witnessing an increasing number of drug-resistant bacteria and viruses. Due to the relevance of the subject, this work presents new methods for the synthesis of biocompatible conjugates of sulfonamides and tetrapyrrolic macrocycles for dual chemo and photodynamic therapy. The combination of these two families of compounds may occur by covalent binding or by self-assembly. Therefore, the work here presented is subdivided. The chapter 1 presents a critical and selected review of the literature underlying to differentstudy topics. The chapter 2 describes a synthetic strategy for preparing tetrapyrrolic macrocycles substituted with sulfonamides by covalent binding. First, we selected 5,10,15,20- tetrakis(pentafluorophenyl)porphyrin as starting material to carry out the methanesulfonamide derivatization optimization studies. Selective synthesis conditions were successfully obtained for the formation of 5-[2’,3’,5’,6’-tetrafluoro-4’-methanesulfamoyl)phenyl]-10,15,20-tri-[(2’,3’,4’,5’,6’- pentafluoro)phenyl]porphyrin (mono-substituted compound) or 5,10,15,20-tetra-[(2’,3’,5’,6’- tetrafluoro-4’-methanesulfamoyl)phenyl]porphyrin (tetra-substituted compound) in 19% and 70 %, yields, respectively. In order to evaluate the effect of the sulfonamide structure in the reactivity, we extended the studies using two sulfonamides previously synthesized in this work as nucleophiles: ptoluenesulfonamide and N-methyl-p-toluenesulfonamide. From this study, it was possible to synthesize and isolate the mono and disubstituted compounds of the p-toluenesulfonamide family (5-[(2’,3’,5’,6’-tetrafluoro-4’-p-toluenesulfamoyl)phenyl]-10,15,20-tri-[(2’,3’,4’,5’,6’- pentafluoro)phenyl]porphyrin, mixture of 5,10-[(2’,3’,5’,6’-tetrafluoro-4’-ptoluenesulfamoyl) phenyl]-15,20-dis-[(2’,3’,4’,5’,6’-pentafluoro)phenyl]porphyrin and 5,15- [(2’,3’,5’,6’-tetrafluoro-4’-p-toluenesulfamoyl)phenyl]-10,20-[(2’,3’,4’,5’,6’- pentafluoro)phenyl]porphyrin) and the mono-, di- and tri-substituted compounds related to substitution with the N-methyl-p-toluenesulfonamide (5-[(2’,3’,5’,6’-tetrafluoro-4’-N-methyl-ptoluenesulfamoyl) phenyl]-10,15,20-tri-[(2’,3’,4’,5’,6’-pentafluoro)phenyl]porphyrin, mixture of 5,10- [(2’,3’,5’,6’-tetrafluoro-4’-N-methyl-p-toluenesulfamoyl)phenyl]-15,20-dis-[(2’,3’,4’,5’,6’-pentafluoro) phenyl]porphyrin and 5,15-[(2’,3’,5’,6’-tetrafluoro-4’-N-methyl-p-toluenesulfamoyl)phenyl]-10,20- [(2’,3’,4’,5’,6’-pentafluoro)phenyl]porphyrin and 5,10,15-tri-[(2’,3’,5’,6’-tetrafluoro-4’-N-methyl-ptoluenesulfamoyl) phenyl]-20-[(2’,3’,4’,5’,6’-pentafluoro)phenyl]porphyrin) in low yields (0.6 to 4.5%). The optimized conditions for the synthesis of tetra-substituted porphyrin were adopted using the N-methyl-p-toluenesulfonamide as nucleophile. We obtained the corresponding 5,10,15,20-tetra[(2',3',5',6'-tetrafluoro-4'-N-methyl-p-toluenesulfamoyl) phenyl]porphyrin in 20% yield . We proceeded with the reduction studies of one of the synthesized porphyrins, using catalytic amounts of ferric chloride hexahydrate (FeCl3·6H2O) and aqueous hydrazine (NH2NH2·H2O), affording the corresponding 5,10,15,20-tetra [2 ', 3', 5 ', 6'-tetrafluoro-4'- methanesulfamoyl) phenyl] chlorin in high yield (65%). Furthermore, we used the solvent free synthetic methodology via reduction with p-toluenesulfonylhydrazide to obtain the 5,10,15,20- tetra[2 ', 3', 5 ', 6'-tetrafluoro-4'- methanesulfamoyl) phenyl]bacteriochlorin in 70% yield. The photophysical assessment shows that the compounds have very promising characteristics to be used as photosensitizers, such as low fluorescence quantum yields (фF≤0.1375) and suitable quantum yields of singlet oxygen formation (фΔ≥0.59). The lipophilicity and the interaction with the lipid membrane was evaluated by calculating the partition coefficient of 5- [2’,3’,5’,6’-tetrafluoro-4’-methanesulfamoyl)phenyl]-10,15,20-tri-[(2’,3’,4’,5’,6’- pentafluoro)phenyl]porphyrin and 5,10,15,20-tetra-[(2’,3’,5’,6’-tetrafluoro-4’- methanesulfamoyl)phenyl]porphyrin using two methods, the octanol/water partition coefficients and lipid unilamellar vesicles (LUVs). From the values obtained, we can assume that the number of metanesulfonamide fragments is crucial to modulate the amphiphilicity of the compounds. While the mono-substituted porphyrin display a logPow>4, the tetra-substituted porphyrin shows a value of log Pow =0.937. Despite these distinct values, both display high lipid membrane affinity. Finally, preliminary in vitro tests with 3T3 fibroblast cell line show that the compound is not toxic. In chapter 3 a methodology based on the self-assembly concept is developed for the preparation of structures containing cationic porphyrins described in bacteria inactivation [5,10,15,20-tetrakis(N-methylpyridinium-4-yl)porphyrinate zinc (II) tetraiodide, 5,10,15,20- tetrakis(1,3-dimethylimidazolium-2-yl) porphyrinate zinc (II) tetraiodide] and Sulfadiazine, a sulfonamide with proven bacteriostatic activity. The chapter 4 presents detailed experimental procedures relating to all the chapters of this thesis, as well as complete chemical characterization of all synthesized compounds (1H NMR, 19F NMR, mass spectrometry and UV-Vis absorption)

Estimating Seroprevalence of SARS-CoV-2 in Ohio: A Bayesian Multilevel Poststratification Approach with Multiple Diagnostic Tests

Globally the SARS-CoV-2 coronavirus has infected more than 59 million people and killed more than 1.39 million. Designing and monitoring interventions to slow and stop the spread of the virus require knowledge of how many people have been and are currently infected, where they live, and how they interact. The first step is an accurate assessment of the population prevalence of past infections. There are very few population-representative prevalence studies of the SARS-CoV-2 coronavirus, and only two American states -- Indiana and Connecticut -- have reported probability-based sample surveys that characterize state-wide prevalence of the SARS-CoV-2 coronavirus. One of the difficulties is the fact that the tests to detect and characterize SARS-CoV-2 coronavirus antibodies are new, not well characterized, and generally function poorly. During July, 2020, a survey representing all adults in the State of Ohio in the United States collected biomarkers and information on protective behavior related to the SARS-CoV-2 coronavirus. Several features of the survey make it difficult to estimate past prevalence: 1) a low response rate, 2) very low number of positive cases, and 3) the fact that multiple, poor quality serological tests were used to detect SARS-CoV-2 antibodies. We describe a new Bayesian approach for analyzing the biomarker data that simultaneously addresses these challenges and characterizes the potential effect of selective response. The model does not require survey sample weights, accounts for multiple, imperfect antibody test results, and characterizes uncertainty related to the sample survey and the multiple, imperfect, potentially correlated tests

Can cardiovascular risk management be improved by shared care with general practice to prevent cognitive decline following stroke/TIA? A feasibility randomised controlled trial (SERVED Memory)

BACKGROUND: Cognitive impairment and dementia following cerebrovascular disease are increasingly common in the UK. One potential strategy to prevent post-stroke cognitive decline is multimodal vascular risk factor management. However, its efficacy remains uncertain and its application in vulnerable patients with incident cerebrovascular disease and early cognitive impairment has not been assessed. The primary aim of this study was to assess the feasibility of recruitment and retention of patients with early cognitive impairment post-stroke or transient ischaemic attack (TIA) to a trial of enhanced vascular risk factor management combining primary and secondary care. METHODS: In this single centre, open label trial adults with a recent stroke or TIA and mild cognitive impairment (MCI) were randomised 1:1 to a three-monthly multimodal vascular risk factor intervention jointly delivered by the trial team and General Practitioner (GP), or control (defined as usual care from the GP). Chosen risk factors were blood pressure (BP), total cholesterol, blood glucose (HbA1C) in those with diabetes, and heart rate and adequacy of anticoagulation in those with atrial fibrillation (AF). Similar patients with normal cognition were enrolled in an embedded observational cohort and also received usual care from the GP. Repeat cognitive screening was undertaken in all participants after 12 months. RESULTS: Seventy three participants were recruited to the randomised trial and 94 to the observational cohort (21.8% of those screened). From the randomised trial 35/73 (47.9%) dropped out before final follow-up. In all groups guideline based rates of risk factor control were mostly poor at baseline and did not significantly improve during follow-up. The observational cohort demonstrated greater decline in cognitive test scores at 12 months, with no difference between the randomised groups. CONCLUSIONS: Recruitment to such a study was feasible, but retention of participants was difficult and generally poor rates of risk factor control suggested insufficient application of the intervention. Consequently, successful scaling up of the trial would require protocol changes with less reliance on primary care services. Any future trial should include participants with normal cognition post-stroke as they may be at greatest risk of cognitive decline. TRIAL REGISTRATION: ISRCTN, ISRCTN42688361 . Registered 16 April 2015

Enhancing the Functionality of a Microscale Bioreactor System as an Industrial Process Development Tool for Mammalian Perfusion Culture

Without a scale-down model for perfusion, high resource demand makes cell line screening or process development challenging; therefore potentially successful cell lines or perfusion processes are unrealised and their ability untapped. We present here the re-functioning of a high capacity microscale system that is typically employed in fed-batch process development to allow perfusion operation utilising in situ gravity settling and automated sampling. In this low resource setting, which involved routine perturbations in mixing, pH and dissolved oxygen concentrations, the specific productivity and the maximum cell concentration were higher than 3.0x106 mg/cell/day and 7x107 cells/ml, respectively, across replicate microscale perfusion runs conducted at one vessel volume exchange per day. A comparative analysis was conducted at bench scale with vessels operated in perfusion mode utilising a cell retention device. Neither specific productivity nor product quality indicated by product aggregation [6%] was significantly different across scales 19 days post inoculation, thus demonstrating this setup to be a suitable and reliable platform for evaluating the performance of cell lines and the effect of process parameters relevant to perfusion mode of culturing

Novel pathogenic COX20 variants causing dysarthria, ataxia, and sensory neuropathy.

COX20/FAM36A encodes a mitochondrial complex IV assembly factor important for COX2 activation. Only one homozygous COX20 missense mutation has been previously described in two separate consanguineous families. We report four subjects with features that include childhood hypotonia, areflexia, ataxia, dysarthria, dystonia, and sensory neuropathy. Exome sequencing in all four subjects identified the same novel COX20 variants. One variant affected the splice donor site of intron-one (c.41A>G), while the other variant (c.157+3G>C) affected the splice donor site of intron-two. cDNA and protein analysis indicated that no full-length cDNA or protein was generated. These subjects expand the phenotype associated with COX20 deficiency

Protocol for a feasibility randomised controlled trial of Screening and Enhanced Risk management for Vascular Event-related Decline in Memory (SERVED Memory)

INTRODUCTION: Stroke is a leading cause of death and disability. The development of dementia after stroke is common. Vascular risk factors (VRF) which contribute to stroke risk can also contribute to cognitive decline, especially in vascular dementia (VaD). There is no established treatment for VaD, therefore strategies for prevention could have major health resource implications. This study was designed to assess whether patients with early cognitive decline after stroke/transient ischaemic attack (TIA) can be easily identified and whether target-driven VRF management can prevent progression to dementia.  OBJECTIVES: The primary objective is to establish the feasibility of recruitment and retention of patients with early cognitive decline to a randomised controlled trial of enhanced VRF management. Secondary objectives include: (a) to determine the potential clinical benefit of the intervention; (b) to estimate the sample size for a future definitive multicentre randomised controlled trial; (c) to inform a future economic evaluation; (d) to explore the link between VRF control and the incidence of cognitive impairment on longitudinal follow-up in a UK population after stroke/TIA with current routine management.  METHODS: 100 patients with cognitive decline poststroke/TIA will be recruited from stroke services at the Norfolk and Norwich University Hospital. After collection of baseline data, they will be randomised to intervention (3 monthly follow-up with enhanced management) or control (treatment as usual by the general practitioner). At 12 months outcomes (repeat cognitive testing, VRF assessment) will be assessed. A further 100 patients without cognitive decline will be recruited to a parallel observational group from the same site. At 12 months they will have repeat cognitive testing.  ETHICS AND DISSEMINATION: Ethical approval has been granted in England. Dissemination is planned via publication in peer-reviewed medical journals and presentation at relevant conferences.  TRIAL REGISTRATION NUMBER: 42688361; Pre-results

Effect of NASA Light-emitting Diode Irradiation on Wound Healing

Objective: The purpose of this study was to assess the effects of hyperbaric oxygen (HBO) and near-infrared light therapy on wound healing. Background Data: Light-emitting diodes (LED), originally developed for NASA plant growth experiments in space show promise for delivering light deep into tissues of the body to promote wound healing and human tissue growth. In this paper, we review and present our new data of LED treatment on cells grown in culture, on ischemic and diabetic wounds in rat models, and on acute and chronic wounds in humans. Materials and Methods: In vitro and in vivo (animal and human) studies utilized a variety of LED wavelength, power intensity, and energy density parameters to begin to identify conditions for each biological tissue that are optimal for biostimulation. Results: LED produced in vitro increases of cell growth of 140–200% in mouse-derived fibroblasts, rat-derived osteoblasts, and rat-derived skeletal muscle cells, and increases in growth of 155–171% of normal human epithelial cells. Wound size decreased up to 36% in conjunction with HBO in ischemic rat models. LED produced improvement of greater than 40% in musculoskeletal training injuries in Navy SEAL team members, and decreased wound healing time in crew members aboard a U.S. Naval submarine. LED produced a 47% reduction in pain of children suffering from oral mucositis. Conclusion: We believe that the use of NASA LED for light therapy alone, and in conjunction with hyperbaric oxygen, will greatly enhance the natural wound healing process, and more quickly return the patient to a preinjury/ illness level of activity. This work is supported and managed through the NASA Marshall Space Flight Center–SBIR Program

Diminished trk A receptor signaling reveals cholinergic‐attentional vulnerability of aging

The cellular mechanisms underlying the exceptional vulnerability of the basal forebrain ( BF ) cholinergic neurons during pathological aging have remained elusive. Here we employed an adeno‐associated viral vector‐based RNA interference ( AAV ‐ RNA i) strategy to suppress the expression of tropomyosin‐related kinase A (trk A ) receptors by cholinergic neurons in the nucleus basalis of M eynert/substantia innominata ( nMB / SI ) of adult and aged rats. Suppression of trk A receptor expression impaired attentional performance selectively in aged rats. Performance correlated with trk A levels in the nMB / SI . trk A knockdown neither affected nMB / SI cholinergic cell counts nor the decrease in cholinergic cell size observed in aged rats. However, trk A suppression augmented an age‐related decrease in the density of cortical cholinergic processes and attenuated the capacity of cholinergic neurons to release acetylcholine ( AC h). The capacity of cortical synapses to release AC h in vivo was also lower in aged/trk A ‐ AAV ‐infused rats than in aged or young controls, and it correlated with their attentional performance. Furthermore, age‐related increases in cortical pro NGF and p75 receptor levels interacted with the vector‐induced loss of trk A receptors to shift NGF signaling toward p75‐mediated suppression of the cholinergic phenotype, thereby attenuating cholinergic function and impairing attentional performance. These effects model the abnormal trophic regulation of cholinergic neurons and cognitive impairments in patients with early A lzheimer's disease. This rat model is useful for identifying the mechanisms rendering aging cholinergic neurons vulnerable as well as for studying the neuropathological mechanisms that are triggered by disrupted trophic signaling. The cellular mechanisms underlying the exceptional vulnerability of the basal forebrain ( BF ) cholinergic neurons during pathological aging have remained elusive. Here we employed an adeno‐associated viral vector‐based RNA interference ( AAV ‐ RNA i) strategy to suppress the expression of trk A receptors by cholinergic neurons in the nucleus basalis of M eynert/substantia innominata (n MB / SI ) of adult and aged rats. This study provides novel evidence that reduced trkA receptors is not sufficient to trigger cholinergic dysfunction. Rather, aging interacts with disrupted trkA signaling to escalate the vulnerability of BF cholinergic neurons and the manifestation of age‐related attentional impairments.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96365/1/ejn12090-sup-0001-SupportingInformation.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/96365/2/ejn12090.pd