Nucleoside Analogues for Positron Emission Tomography Imaging and to Study Radiation Mediated Generation of Radicals from Azides

Gemcitabine is a potent anticancer cytidine analogue used to treat solid tumors. Its efficacy is diminished by rapid deamination to a toxic uridine derivative by cytidine deaminase. To overcome this limitation and add radioactive nuclei (18F or 68Ga) for PET imaging, I synthesized two 4-N­-alkylgemcitabine analogues i) bearing β-keto tosylate moiety for subsequent 18F-fluorination and ii) having SCN-Bn-NOTA chelator to complex 68Ga. The first was synthesized by replacement of tosylamide in 4-N­-tosylgemcitabine with 1-amino-10-undecene, followed by elaboration of terminal alkene through dihydroxylation, regioselective tosylation and oxidation. Subsequent fluorination using KF in presence of 18-Crown-6 at 75°C for 1 hr gave 4-N­-alkylgemcitabine fluoromethyl ketone. The second was synthesized by analogous replacement of tosylamide with N-Boc-1,3-propanediamine, followed by deprotection with TFA. The reactive terminal amine was condensed with SCN-Bn-NOTA, giving 4-N­-alkylgemcitabine-SCN-Bn-NOTA ligand, which efficiently complexed Ga or 68Ga for in vivo PET studies in rats. Clofarabine is a highly effective chemotherapeutic adenosine analogue used for treatment of acute lymphoblastic leukemia. Clofarabine undergoes rate limiting phosphorylation from its 5\u27-monophosphate to 5\u27-diphosphate by purine monophosphate kinase, and possible dephosphorylation of its respective 5\u27-monophosphate by 5\u27-nucleotidases. Synthesis of clofarabine diphosphate prodrugs, and potentially their 18F-radiolabeled analogues, were undertaken to overcome these limitations. Successful synthesis of model adenosine diphosphate prodrug, by coupling adenosine monophosphate with bis(benzoyloxybenzyl) phosphoramidite in presence of 5-phenyl-1-H­-tetrazole activator was achieved. The aminyl radical generated from azide moiety in 3\u27-azido-3\u27-deoxythymidine (3\u27-AZT) or 5-azidomethyl-2\u27-deoxyuridine (AmdU), upon addition of radiation-produced electrons, is thought to be the source of their radiosensitizing effects. Herein, I report synthesis of azido-modified purine and pyrimidine analogues for EPR study of formation of reactive aminyl radical in guanine, adenine and cytidine bases. The EPR studies of electron addition to 2-azidoguanosine (i.e. 2-azidoinsoine), protected 4-azidocytidine and 4-tetrazolocytidine analogues clearly establish that the position of the azide in base moiety dictates reactivity. The azide directly attached to nucleobases at ortho/para position to ring nitrogens produce stable RN3•- that does not rapidly convert to aminyl radical, except in the excited state. Hence, these did not display much radiosensitizing effects in in vivo biological studies in MDA-MB-231, MCF7 and U87 cell lines

Intra-arterial adenoviral mediated tumor transfection in a novel model of cancer gene therapy

BACKGROUND: The aim of the present study was to develop and characterize a novel in vivo cancer gene therapy model in which intra-arterial adenoviral gene delivery can be characterized. In this model, the rat cremaster muscle serves as the site for tumor growth and provides convenient and isolated access to the tumor parenchyma with discrete control of arterial and venous access for delivery of agents. RESULTS: Utilizing adenovirus encoding the green fluorescent protein we demonstrated broad tumor transfection. We also observed a dose dependant increment in luciferase activity at the tumor site using an adenovirus encoding the luciferase reporter gene. Finally, we tested the intra-arterial adenovirus dwelling time required to achieve optimal tumor transfection and observed a minimum time of 30 minutes. CONCLUSION: We conclude that adenovirus mediated tumor transfection grown in the cremaster muscle of athymic nude rats via an intra-arterial route could be achieved. This model allows definition of the variables that affect intra-arterial tumor transfection. This particular study suggests that allowing a defined intra-tumor dwelling time by controlling the blood flow of the affected organ during vector infusion can optimize intra-arterial adenoviral delivery

Pulmonary non-tuberculous mycobacterial infections: current state and future management

Currently, there is a trend of increasing incidence in pulmonary non-tuberculous mycobacterial infections (PNTM) together with a decrease in tuberculosis (TB) incidence, particularly in developed countries. The prevalence of PNTM in underdeveloped and developing countries remains unclear as there is still a lack of detection methods that could clearly diagnose PNTM applicable in these low-resource settings. Since non-tuberculous mycobacteria (NTM) are environmental pathogens, the vicinity favouring host-pathogen interactions is known as important predisposing factor for PNTM. The ongoing changes in world population, as well as socio-political and economic factors, are linked to the rise in the incidence of PNTM. Development is an important factor for the improvement of population well-being, but it has also been linked, in general, to detrimental environmental consequences, including the rise of emergent (usually neglected) infectious diseases, such as PNTM. The rise of neglected PNTM infections requires the expansion of the current efforts on the development of diagnostics, therapies and vaccines for mycobacterial diseases, which at present, are mainly focused on TB. This review discuss the current situation of PNTM and its predisposing factors, as well as the efforts and challenges for their control

Affordance-Aware Handovers With Human Arm Mobility Constraints

Reasoning about object handover configurations allows an assistive agent to estimate the appropriateness of handover for a receiver with different arm mobility capacities. While there are existing approaches for estimating the effectiveness of handovers, their findings are limited to users without arm mobility impairments and to specific objects. Therefore, current state-of-the-art approaches are unable to hand over novel objects to receivers with different arm mobility capacities. We propose a method that generalises handover behaviours to previously unseen objects, subject to the constraint of a user's arm mobility levels and the task context. We propose a heuristic-guided hierarchically optimised cost whose optimisation adapts object configurations for receivers with low arm mobility. This also ensures that the robot grasps consider the context of the user's upcoming task, i.e., the usage of the object. To understand preferences over handover configurations, we report on the findings of an online study, wherein we presented different handover methods, including ours, to $259$ users with different levels of arm mobility. We find that people's preferences over handover methods are correlated to their arm mobility capacities. We encapsulate these preferences in a statistical relational model (SRL) that is able to reason about the most suitable handover configuration given a receiver's arm mobility and upcoming task. Using our SRL model, we obtained an average handover accuracy of $90.8\%$ when generalising handovers to novel objects.Comment: Accepted for RA-L 202

HSE Management for a Sound Work Environment: Strategies for Improving Health Safety and Environmental Indicators through Ergonomic Design Thinking

Ergonomic Design Thinking (EDT) is a project management methodology that takes advantage of two important concepts or themes in carrying out project actions. The first is Design Thinking itself, a project management approach originally proposed by Tim Brown, who knew beforehand the full potential of design tools, techniques and maybe we should add idiosyncrasies. Designers have “their own way” of following through and carrying out issues such as deadlines and sequences, for example. This logic is similar to another important theme: ergonomics. The main objective of ergonomics is adapting work systems to workers themselves. By doing so, its professionals dig deep into the social technical fabric of a workplace and use recurrent and iterative strategies in order to search for a perfect fit for a given workstation. EDT as a modeling guide for workspace projects have been used in Brazil for quite some time. This text outlines an interesting experience in which EDT was used as a conception tool in building a new health safety and environmental (HSE) management system model for construction sites. A real case–an ongoing construction work–was used to contextualize the experiment and better define the various instruments of this HSE model. Due to the work environment and predominant job characteristics available, the EDT approach did quite well in terms of serving its project management purpose, as it was confirmed when the new system became fully functional

Repro Money: An Extension Program to Improve Dairy Farm Reproductive Performance

A farmer-directed, team-based Extension program (Repro Money) was developed and executed by the University of Wisconsin–Madison Department of Dairy Science in collaboration with University of Wisconsin–Extension. The goal of the Repro Money program was to help Wisconsin dairy farmers increase reproductive performance and profitability through identification of areas for improvement and implementation of action plans. For the 40 Wisconsin dairy farms that completed the Repro Money program, mean 21-day pregnancy rate increased by 2 percentage points, which was estimated to result in an economic net gain of $31 per cow per year. Extension professionals can apply similar team-based programs to tackle multifaceted, interrelated problems that may be only partially addressed by other, more traditional programming

Addressing the disparities in dementia risk, early detection and care in Latino populations: Highlights from the second Latinos & Alzheimer\u27s Symposium

The Alzheimer\u27s Association hosted the second Latinos & Alzheimer\u27s Symposium in May 2021. Due to the COVID-19 pandemic, the meeting was held online over 2 days, with virtual presentations, discussions, mentoring sessions, and posters. The Latino population in the United States is projected to have the steepest increase in Alzheimer\u27s disease (AD) in the next 40 years, compared to other ethnic groups. Latinos have increased risk for AD and other dementias, limited access to quality care, and are severely underrepresented in AD and dementia research and clinical trials. The symposium highlighted developments in AD research with Latino populations, including advances in AD biomarkers, and novel cognitive assessments for Spanish-speaking populations, as well as the need to effectively recruit and retain Latinos in clinical research, and how best to deliver health-care services and to aid caregivers of Latinos living with AD

New insights into phenotype and genotype relationships in Neospora caninum

The successful isolation of four new Neospora caninum strains from different regions and with different backgrounds (obtained from an abortion storm or congenitally infected and asymptomatic calves) allowed us previously to characterize natural isolates, finding differences in phenotype and microsatellites. Given the variability observed, we wondered in this work whether these differences had consequences in virulence, invasion and vertical transmission using cell cultures and murine neosporosis models. In addition, we performed the genomic analysis and SNP comparative studies of the NcURU isolates. The results obtained in this work allowed us to establish that NcURU isolates are of low virulence and have unique phenotypic characteristics. Likewise, sequencing their genomes has allowed us to delve into the genetic singularities underlying these phenotypes, as well as the common mutated genes. This work opens a new perspective for diagnostic purposes and formulating possible vaccines based on attenuated strains

Tribromuro de benzalconio . Sántesis y utilizacién en procesos de bromacién de fenoles .

La bromación clásica de substratos aromáticos exige la utilización de dibromo (Br2), tóxico, contaminante y de difícil manipulación, así como de catalizadores costosos que generan residuales con gran impacto ambiental. En los «últimos años se han introducido catalizadores más regioselectivos pero requieren la utilización de dibromo para su preparación. Las sales tribromadas de amonio como tribromuro de piridinio y tribromuro de feniltrimetilamonio se han empleado como agentes bromantes suaves. Estos reactivos pueden utilizarse cuantitativamente en forma sólida, lo que facilita su manipulación. En la presente comunicación se reporta una sencilla vía sintética para la obtención de bromofenoles utilizando como agente halogenante tribromuro de benzalconio (Benzal-Br3). Este compuesto es obtenido a partir de cloruro de benzalconio comercialmente asequible y su tratamiento con NaBrO3-HBr en diclorometano en condiciones sencillas y con satisfactorios rendimientos. Mediante técnicas FTIR y RMN 'H y "C se corrobora la estructura propuesta para este perbromuro. La reacción de substratos fenólicos con Benzal-Br3 en diclorometano-metanol durante 1-4h a temperatura ambiente permite obtener los bromoderivados correspondientes (> 75%). Este procedimiento permite, sin condiciones especiales, obtener una serie de fenoles bromosubstituidos en dependencia de las relaciones molares utilizadas del agente bromante (1 :1; 2 :1; 3 :1) vs substrato fenólico