Publications by authors named "John O'Brien"

Human UDP-glucose dehydrogenase (hUGDH) catalyzes the oxidation of UDP-glucose into UDP-glucuronic acid, an essential substrate in the Phase II metabolism of drugs. hUGDH is a hexamer that exists in an equilibrium between an active (E) state and an inactive (E) state, with the latter being stabilized by the binding of the allosteric inhibitor UDP-xylose (UDP-Xyl). The allosteric transition between E and E is slow and can be observed as a lag in progress curves.

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Through decades of research, we have gained a comprehensive understanding of the protein complexes underlying function and regulation of chemical synapses in the nervous system. Despite the identification of key molecules such as ZO-1 or CaMKII, we currently lack a similar level of insight into the electrical synapse proteome. With the advancement of BioID as a tool for proteomics, it has become possible to identify complex interactomes of a given protein of interest by combining enzymatic biotinylation with subsequent streptavidin affinity capture.

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Background: Genetic risk factors start to affect the brain and behavior in Alzheimer's disease (AD) before clinical symptoms occur. Although AD is mainly associated with memory deficits, attention and executive dysfunctions can present at the early presymptomatic stages in middle age for those with non-modifiable risks.

Objective: Here, we investigated whether known risk genes for AD already affected attention in young adulthood.

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Article Synopsis
  • The study aimed to assess changes in cardiac [123I]-metaiodobenzylguanidine uptake in individuals with mild cognitive impairment with Lewy bodies (MCI-LB) who initially had normal scans.
  • Eight participants underwent follow-up scans 2 to 4 years after their baseline assessments, with all repeat scans also returning normal results.
  • Despite normal scans, three participants showed a significant decrease in uptake (over 10%) and the overall mean change in uptake was a decline of 5.2%.
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  • - Brain Age Gap is related to dementia in older adults, but its link to dementia risk-factors and cognitive performance in middle-aged individuals is less explored.
  • - A study involving 552 cognitively healthy middle-aged participants showed that brain age gap correlates with factors like hypertension and alcohol intake, but not with genetic risk factors (like the APOE ε4 allele) or cognitive performance.
  • - Findings suggest that addressing modifiable risk factors may help in developing therapies to prevent dementia in middle-aged populations.
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  • This study examined attention deficits in Lewy body dementia (LBD) and Alzheimer's disease (AD) using fMRI and EEG technology.
  • It involved 33 LBD patients, 15 AD patients, and 19 healthy elderly controls performing a modified Attention Network Task (ANT).
  • The findings revealed distinct attention dysfunctions: LBD exhibited alerting deficits while AD showed impairments in orienting attention, with specific neural activity patterns unique to each condition.
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  • Caregiver histories are valuable for diagnosing neurodegenerative diseases; the study analyzed 4952 caregiver questionnaires from 2481 participants.
  • Using advanced machine learning, researchers achieved high diagnostic accuracy (mean AUC 0.83) between different diseases, while observing changes in symptoms over time.
  • The findings stress the importance of structured caregiver reports for diagnosing dementia and suggest the Cambridge Behavioural Inventory can effectively track disease progression in clinical settings.
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Objectives: To describe (1) rebate arrangements for specialty drugs, (2) the use and influence of benefits brokers and consultants, and (3) the importance of rebate-related factors when selecting a pharmacy benefits manager (PBM) among a sample of employers with self-funded pharmacy benefits.

Study Design: A national survey of employer drug benefit decision makers (N = 110) for organizations with self-insured pharmacy benefits.

Methods: We summarized respondents' current rebate agreements for specialty drugs and their perspectives on the importance of rebates and rebate guarantees overall as well as by type of rebate agreement and by the person or entity identified as most influential in rebate strategy.

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Inflammation is an important risk factor, a potential therapeutic target for cognitive decline and dementia, and an inherent feature of autoimmune and immune-mediated rheumatic diseases. The risk of cognitive impairment and dementia is increased in individuals with immune-mediated rheumatic diseases, particularly in those with cardiovascular risk factors and cardiovascular disease. Immunomodulatory medications have been associated with a reduced risk of dementia, but whether this effect is mediated through their anti-inflammatory immunomodulating properties or other mechanisms, such as cardiovascular risk reduction, is unclear.

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Unlike their planar counterparts, classic synthetic protocols for C-C bond forming reactions on nonplanar porphyrins are underdeveloped. The development of C-C bond forming reactions on nonplanar porphyrins is critical in advancing this field of study for more complex porphyrin architectures, which could be used in supramolecular assemblies, catalysis, or sensing. In this work a library of arm-extended dodecasubstituted porphyrins was synthesized through the optimization of the classic Suzuki-Miyaura coupling of peripheral haloaryl substituents with a range of boronic acids.

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The innate immune system plays an integral role in the progression of many neurodegenerative diseases. In addition to central innate immune cells (e.g.

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Article Synopsis
  • Gap junctions made by the connexin Cx36 are crucial for electrical signaling between neurons, helping synchronize their activities and support network oscillations.
  • The transport pathways of Cx36 from the endoplasmic reticulum (ER) to the Golgi apparatus are investigated using HEK293T cells, revealing the importance of its C-terminal region in binding to the COPII complex and the Golgi stacking protein Grasp55.
  • The C-terminal valine functions as a signal for ER export, aiding in Cx36's movement from the ER, while Grasp55 helps stabilize Cx36 in the Golgi, both of which play significant roles in the regulation and formation of electrical synapses in the nervous system.
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Introduction: Recent research has raised questions about potential unintended consequences of the Inflation Reduction Act's Drug Price Negotiation Program (DPNP), suggesting that the timelines introduced by the law may reduce manufacturer incentives to invest in post-approval research towards additional indications. Given the role of multiple indications in expanding treatment options in patients with cancer, IRA-related changes to development incentives are especially relevant in oncology. This study aimed to describe heterogeneous drug-level trajectories and timelines of subsequent indications in a cohort of recently approved, multi-indication oncology drugs, including overall, across subgroups of drugs characterized by the timing and pace of additional indications, and by drug type (i.

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Background And Objectives: Vascular risk factors (VRFs) and cerebral small vessel disease (cSVD) are common in patients with Alzheimer disease (AD). It remains unclear whether this coexistence reflects shared risk factors or a mechanistic relationship and whether vascular and amyloid pathologies have independent or synergistic influence on subsequent AD pathophysiology in preclinical stages. We investigated links between VRFs, cSVD, and amyloid levels (Aβ) and their combined effect on downstream AD biomarkers, that is, CSF hyperphosphorylated tau (P-tau), atrophy, and cognition.

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: The pathophysiology of Alzheimer's disease (AD) may begin developing years or even decades prior to the manifestation of its first symptoms. The APOE ε4 genotype is a prominent genetic risk for AD that has been found to be associated with brain changes across the lifespan since early adulthood. Thus, studying brain changes that may occur in young adults with an APOE ε4 status is highly relevant.

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Background: Neuropsychiatric symptoms are common in dementia and linked to adverse outcomes. Inflammation is increasingly recognized as playing a role as a driver of early disease progression in Alzheimer's disease (AD) and related dementias. Inflammation has also been linked to primary psychiatric disorders, however its association with neuropsychiatric symptoms in neurodegenerative dementias remains uncertain.

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Neuroinflammation is an important pathogenic mechanism in many neurodegenerative diseases, including those caused by frontotemporal lobar degeneration (FTLD). Postmortem and in vivo imaging studies have shown brain inflammation early in these conditions, proportionate to symptom severity and rate of progression. However, evidence for corresponding blood markers of inflammation and their relationship with central inflammation and clinical outcome are limited.

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This commentary explores how 2 recently published studies evaluating the clinical benefit of the FDA's accelerated approval program for oncology drugs came to different conclusions.

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Importance: Traumatic brain injuries (TBI) represent an important, potentially modifiable risk factor for dementia. Despite frequently observed vascular imaging changes in individuals with TBI, the relationships between TBI-associated changes in brain imaging and clinical outcomes have largely been overlooked in community cases of TBI.

Objective: To assess whether TBI are associated with and interact with midlife changes in neuroimaging and clinical features in otherwise healthy individuals.

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Introduction: We tested associations between two retinal measures (optic disc pallor, peripapillary retinal nerve fiber layer [pRNFL] thickness) and four magnetic resonance imaging markers of cerebral small vessel disease (SVD; lacunes, microbleeds, white matter hyperintensities, and enlarged perivascular spaces [ePVSs]).

Methods: We used PallorMetrics to quantify optic disc pallor from fundus photographs, and pRNFL thickness from optical coherence tomography scans. Linear and logistic regression assessed relationships between retinal measures and SVD markers.

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Overexpression of proteins in transiently transfected cells is a simple way to study basic transport mechanisms and the underlying protein-protein interactions. While expression systems have obvious drawbacks compared to in vivo experiments, they allow a quick assessment of more conserved functions, for instance, ER export or sorting of proteins in the Golgi. In a previous study, our group described the formation of ER-derived removal vesicles for the gap junction protein Cx36 in transfected HEK293T cells.

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Brain atrophy and cortical thinning are typically observed in people with Alzheimer's disease (AD) and, to a lesser extent, in those with mild cognitive impairment. In asymptomatic middle-aged apolipoprotein ε4 (ΑPOE4) carriers, who are at higher risk of future AD, study reports are discordant with limited evidence of brain structural differences between carriers and non-carriers of the ε4 allele. Alternative imaging markers with higher sensitivity at the presymptomatic stage, ideally quantified using typically acquired structural MRI scans, would thus be of great benefit for the detection of early disease, disease monitoring and subject stratification.

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Article Synopsis
  • The study explores the genetic risk factors for Alzheimer's disease (AD) and their connection to various brain changes, aiming to enhance precision medicine strategies.
  • Researchers calculated specific genetic risk scores in healthy individuals to see how these scores correlate with AD-related biomarkers found in cerebrospinal fluid and imaging techniques.
  • Findings show that different genetic pathways link to distinct brain conditions, such as inflammation affecting vascular health and other pathways influencing white matter and brain connectivity, highlighting the complexity of AD and its potential for personalized treatment approaches.
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Background Impaired glucose metabolism is characteristic of several types of dementia, preceding cognitive symptoms and structural brain changes. Reduced glucose uptake in specific brain regions, detected using fluorine 18 (F) fluorodeoxyglucose (FDG) PET, is a valuable diagnostic marker in Alzheimer disease (AD). However, the use of F-FDG PET in clinical practice may be limited by equipment availability and high cost.

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