Your voice matters: Assessing the need for a resource center

With the transformation of the AGEP project initiative, identifying and preserving the knowledge created and making it available for re-use by other researchers and higher education institutions will require the development of a specific intervention. The current trajectory for the Alliances materials will fail to reach the larger audiences needed to realize their full promise and the materials will be lost over time due to the absence of infrastructure to provide ongoing access

Targeting the HSP60/10 chaperonin systems of Trypanosoma brucei as a strategy for treating African sleeping sickness

Trypanosoma brucei are protozoan parasites that cause African sleeping sickness in humans (also known as Human African Trypanosomiasis—HAT). Without treatment, T. brucei infections are fatal. There is an urgent need for new therapeutic strategies as current drugs are toxic, have complex treatment regimens, and are becoming less effective owing to rising antibiotic resistance in parasites. We hypothesize that targeting the HSP60/10 chaperonin systems in T. brucei is a viable anti-trypanosomal strategy as parasites rely on these stress response elements for their development and survival. We recently discovered several hundred inhibitors of the prototypical HSP60/10 chaperonin system from Escherichia coli, termed GroEL/ES. One of the most potent GroEL/ES inhibitors we discovered was compound 1. While examining the PubChem database, we found that a related analog, 2e-p, exhibited cytotoxicity to Leishmania major promastigotes, which are trypanosomatids highly related to Trypanosoma brucei. Through initial counter-screening, we found that compounds 1 and 2e-p were also cytotoxic to Trypanosoma brucei parasites (EC50 = 7.9 and 3.1 μM, respectively). These encouraging initial results prompted us to develop a library of inhibitor analogs and examine their anti-parasitic potential in vitro. Of the 49 new chaperonin inhibitors developed, 39% exhibit greater cytotoxicity to T. brucei parasites than parent compound 1. While many analogs exhibit moderate cytotoxicity to human liver and kidney cells, we identified molecular substructures to pursue for further medicinal chemistry optimization to increase the therapeutic windows of this novel class of chaperonin-targeting anti-parasitic candidates. An intriguing finding from this study is that suramin, the first-line drug for treating early stage T. brucei infections, is also a potent inhibitor of GroEL/ES and HSP60/10 chaperonin systems

The synergistic effects of saxagliptin and metformin on CD34+ endothelial progenitor cells in early type 2 diabetes patients: a randomized clinical trial.

AIMS: Type 2 diabetes is associated with endothelial dysfunction leading to cardiovascular disease. CD34+ endothelial Progenitor Cells (EPCs) are responsible for endothelial repair and neo-angiogenesis and can be used as a cardiovascular disease risk biomarker. This study investigated whether the addition of saxagliptin, a DPP-IV inhibitor, to metformin, may reduce cardiovascular disease risk in addition to improving glycemic control in Type 2 diabetes patients. METHODS: In 12 week, double-blind, randomized placebo-controlled trial, 42 subjects already taking metformin 1-2 grams/day were randomized to placebo or saxagliptin 5 mg. Subjects aged 40-70 years with diabetes for \u3c 10 years, with no known cardiovascular disease, BMI 25-39.9, HbA1C 6-9% were included. We evaluated EPCs number, function, surface markers and gene expression, in addition to arterial stiffness, blood biochemistries, resting energy expenditure, and body composition parameters. A mixed model regression to examine saxagliptin vs placebo, accounting for within-subject autocorrelation, was done with SAS (p \u3c 0.05). RESULTS: Although there was no significant increase in CD34+ cell number, CD31+ cells percentage increased. Saxagliptin increased migration (in response to SDF1α) with a trend of higher colony formation count. MNCs cytometry showed higher percentage of CXCR4 double positivity for both CD34 and CD31 positive cells, indicating a functional improvement. Gene expression analysis showed an upregulation in CD34+ cells for antioxidant SOD1 (p \u3c 0.05) and a downregulation in CD34- cells for IL-6 (p \u3c 0.01). For arterial stiffness, both augmentation index and systolic blood pressure measures went down in saxagliptin subjects (p \u3c 0.05). CONCLUSION: Saxagliptin, in combination with metformin, can help improve endothelial dysfunction in early diabetes before macrovascular complications appear. Trial registration Trial is registered under clinicaltrials.gov, NCT02024477

Development and characterization of a novel conductive polyaniline-g-polystyrene/Fe 3 O 4 nanocomposite for the treatment of cancer

The goal of this study is to synthesize, characterize and investigate some physicochemical properties of conductive polyaniline-g-polystyrene/Fe 3 O 4 (Fe 3 O 4 /PSt-g-PANi) nanocomposites. For this purpose, initially, Fe 3 O 4 nanoparticles were synthesized by a co-precipitation method. Then, the desired nanocomposite was synthesized in two steps. First, the atom transfer radical polymerization (ATRP) of styrene was performed using an ATRP initiator attached to the surface of Fe 3 O 4 nanoparticles, followed by functionalization of the Fe 3 O 4 -PSt with amine groups (�NH 2 ). Second, surface oxidative graft copolymerization of aniline was accomplished using the �NH 2 moieties on the Fe 3 O 4 /PSt-NH 2 as the anchoring sites. The prepared materials were characterized by various instruments, including TEM, SEM, TGA, EDX, FT-IR, XRD and conductivity measurements. The results indicated that the synthesized conductive polymer/Fe 3 O 4 nanocomposites had higher electrical conductivity and thermal resistance than those of the corresponding homopolymers. © 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group

A single-center observational study on long-term neurodevelopmental outcomes in children with tuberous sclerosis complex

Abstract Background Tuberous sclerosis complex (TSC) is a rare multisystem disorder caused by mutations in the TSC1 or TSC2 gene. More than 90% of patients with TSC develop neurological and/or neuropsychiatric manifestations. The aim of the present study was to determine the developmental and cognitive long-term outcomes of pediatric TSC patients. Methods This cross-sectional, monocenter study included pediatric TSC patients who received multidisciplinary long-term care with a last visit between 2005 and 2019. Neurological manifestations and cognitive development (BSID, K-ABC) were analyzed in relation to age and type of mutation. Results Thirty-five patients aged 13.5 ± 7.8 years were included in the study. Diagnosis was confirmed genetically in 65.7% of patients (TSC1, 26.1%; TSC2, 65.2%; NMI, 8.7%). Mean age at diagnosis was 1.3 ± 3.5 years; 74.3% of the patients had been diagnosed within the first year of life due to seizures (62.9%) or/and cardiac rhabdomyomas (28.6%). The most common TSC manifestations included structural brain lesions (cortical tubers, 91.4%; subependymal nodules, 82.9%), epilepsy (85.7%), and cardiac rhabdomyomas (62.9%). Mean age at seizure onset was 1.5 ± 2.3 years, with onset in 80.0% of patients within the first two years of life. Infantile spasms, which were the first seizure type in 23.3% of the patients, developed earlier (0.6 ± 0.4 years) than focal seizures (1.8 ± 2.5 years). Refractory epilepsy was present in 21 (70.0%) patients, mild or severe intellectual impairment in 66.6%, and autism spectrum disorders in 11.4%. Severe cognitive impairment (33.3%) was significantly associated with epilepsy type and age at seizure onset (p &lt; 0.05). Conclusions The results emphasized the phenotypic variability of pediatric-onset TSC and the high rate of neurological and neuropsychiatric morbidity. Early-onset refractory epilepsy was associated with impaired cognitive development. Children of all ages with TSC require multidisciplinary long-term care and individual early-intervention programs. </jats:sec

Reduced Retinal Thickness Predicts Age-Related Changes in Cognitive Function

Currently, there is a lack of biomarkers to identify individuals in the early stages of Alzheimer’s disease (AD). A preponderance of evidence suggests that neurodegenerative processes that affect the brain, may also affect the retina. Using optical coherence tomography (OCT), a non-invasive approach, many have shown thinning of the retina in AD and the developmental precursor to AD, mild cognitive impairment (MCI). However, the relationship between retinal thickness and cognitive function is not entirely clear. This is likely due to the disparity in diagnostic criteria used to determine MCI that does not fully probe the cognitive domains that are particularly vulnerable to aging. This study used a comprehensive neuropsychological assessment involving multiple domains of cognition to determine if retinal thickness correlates with cognitive performance in a normal aged population. In this study, 20 healthy individuals between 60 and 90 years of age were administered neuropsychological assessments probing various domains of cognitive function, and OCT to measure peripapillary retinal nerve fiber layer (RNFL) thickness. We found that RNFL thickness is correlated with neuropsychological performance in multiple cognitive domains (e.g., working memory, psychomotor speed, and executive function). Our work demonstrates a positive correlation between RNFL thickness and several, but not all, domains of cognitive function in a normative aging population. By determining which cognitive domains retinal thickness can predict, this work can help identify individuals at risk or in preclinical stages of AD and other neurodegenerative diseases.This article is published as Mammadova, N., Neppl, T. K., Denburg, N. L., & Greenlee, M. H. W. (2020). Reduced retinal thickness predicts age-related changes in cognitive function. Frontiers in Aging Neuroscience, 12; 81. DOI: 10.3389/fnagi.2020.00081. Posted with permission. © 2020 Mammadova, Neppl, Denburg and West Greenlee. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.<br