Faculty Bibliography
Searched for:
school:SOM
Department/Unit:Neuroscience Institute
Total Results:
13348
Switching to e-cigarettes as harm reduction among individuals with chronic disease who currently smoke: Results of a pilot randomized controlled trial
INTRODUCTION/BACKGROUND:E-cigarettes (ECs) may be an effective harm reduction strategy for individuals with conditions like chronic obstructive pulmonary disease (COPD), asthma, coronary artery disease (CAD), and peripheral arterial disease (PAD) who smoke combustible cigarettes (CCs). Our aim was to examine how individuals with chronic conditions transition from CCs to ECs and its impact on health outcomes. METHODS:In a pilot randomized controlled trial (RCT), patients with COPD, asthma, CAD/PAD who currently smoke CCs and have not used nicotine replacement therapy (NRT) or ECs in the past 14 days were randomized to receive ECs or combination NRT with behavioral counselling. Disease symptoms, acceptability/satisfaction (TSQM-9) and feasibility, and cigarettes per day (CPD), and/or EC use were collected at baseline, 3-, and 6-months. Descriptive statistics and a linear regression were conducted to explore changes in CPD and chronic condition-specific assessments (CAT, SAQ-7, ACT) that assess COPD, asthma, and CAD/PAD symptom change. RESULTS:At 3-months, the EC group (n=63, mean CPD=9±11) reduced their CPD by 54% vs. 60% in the NRT group (n=58, mean CPD=7±6), p=0.56. At 6-months, 17.5% had switched completely to ECs while 23% quit smoking in the NRT arm. CAT scores showed a significant 6-point reduction in the EC arm (p=0.03). Participants scored an average of 69±27 for EC effectiveness, 87±23 for convenience, and 75±27 for overall satisfaction. CONCLUSIONS:This pilot study suggests that ECs may be a safer alternative for chronic condition patients using CCs and warrants further research on expected smoking cessation/reduction among individuals who use ECs. IMPLICATIONS/CONCLUSIONS:The findings from this pilot RCT hold significant implications with chronic conditions such as COPD, asthma, CAD and PAD who smoke CCs. The observed reduction in cigarettes per day and improvement in respiratory symptoms suggest that switching to ECs appears feasible and acceptable among those with chronic diseases. These results suggest that ECs may offer an alternative for individuals struggling to quit CC smoking through existing pharmacotherapies. This study supports further exploration of switching to ECs as a harm reduction strategy among CC users who have been unsuccessful at quitting by other means.
PMID: 38995184
ISSN: 1469-994x
CID: 5732502
Transsynaptic modulation of cerebellar nuclear cells: theta AC-burst stimulation
PMCID:11638969
PMID: 39637565
ISSN: 1741-2552
CID: 5762182
Stress and Parental Behaviors
In nearly all mammalian species, newborn pups are weak and vulnerable, relying heavily on care and protection from parents for survival. Thus, developmentally hardwired neural circuits are in place to ensure the timely expression of parental behaviors. Furthermore, several neurochemical systems, including estrogen, oxytocin, and dopamine, facilitate the emergence and expression of parental behaviors. However, stress can adversely affect these systems, impairing parental behaviors. In this review, we will summarize our current knowledge regarding the impact of stress on pup-directed behavior circuits that lead to infant neglect, abuse, and, in extreme cases, killing. We will discuss various stressors that influence parental behaviors at different life stages and how stress induces changes in the neurochemical systems that support parental care, ultimately leading to its poor performance.
PMID: 39674404
ISSN: 1872-8111
CID: 5762052
Inositol 1,4,5-Trisphosphate Receptor 1 Gain-of-Function Increases the Risk for Cardiac Arrhythmias in Mice and Humans
BACKGROUND/UNASSIGNED:handling and arrhythmia susceptibility. METHODS/UNASSIGNED:There are a large number of rare ITPR1 missense variants reported in open data repositories. Based on their locations in the ITPR1 channel structure, we selected and characterized 33 human ITPR1 missense variants from open databases and identified 21 human ITPR1 GOF variants. We generated a mouse model carrying a human ITPR1 GOF variant, ITPR1-W1457G (W1447G in mice). RESULTS/UNASSIGNED:release, delayed afterdepolarization, and triggered activity in Purkinje cells. To assess the potential role of ITPR1 variants in arrhythmia susceptibility in humans, we looked up a gene-based association study in the UK Biobank data set and identified 7 rare ITPR1 missense variants showing potential association with cardiac arrhythmias. Remarkably, in vitro functional characterization revealed that all these 7 ITPR1 variants resulted in GOF. CONCLUSIONS/UNASSIGNED:Our studies in mice and humans reveal that enhanced function of ITPR1, a well-known movement disorder gene, increases the risk for cardiac arrhythmias.
PMID: 39655431
ISSN: 1524-4539
CID: 5762482
Programmed Cell Death Protein 1 Contributes to Oral Cancer Pain via Regulating Tumor Necrosis Factor Alpha in the Spinal Trigeminal Nucleus Caudalis
BACKGROUND:Oral cancer causes intense pain at the primary site, and such pain can impair oral functions. However, the underlying mechanisms for oral cancer pain are still not fully understood. In the present study, it is investigated whether programmed cell death protein 1 (PD-1) is involved in the development of oral cancer pain. METHODS:RMP1-14, a specific anti-PD-1 antibody, was injected into spinal trigeminal nucleus caudalis (Sp5C) and measured pain behaviors using von Frey filaments and dolognawmeter. Western blotting and immunofluorescence staining were performed to analyze the expression of PD-1 and tumor necrosis factor alpha (TNFα) in the Sp5C. RESULTS:It was observed that the PD-1 antibody significantly inhibited mechanical hypersensitivity and functional allodynia in our oral cancer pain mouse model. Moreover, we found that TNFα was highly upregulated in the Sp5C following the induction of oral cancer pain and that intra-Sp5C injection of the PD-1 antibody diminished the upregulation of TNFα. It was found that genetic deletion of TNFα or its receptor antagonism synergized the analgesic effect of PD-1 antibody on oral cancer pain. CONCLUSION/CONCLUSIONS:Our results suggest that PD-1 in the Sp5C contributes to oral cancer pain by altering TNFα signaling in the trigeminal nociceptive system, and PD-1 could be targeted to develop a novel approach for oral cancer pain management.
PMID: 39660489
ISSN: 1875-6190
CID: 5766032
Neuroinflammation in Alzheimer disease
Increasing evidence points to a pivotal role of immune processes in the pathogenesis of Alzheimer disease, which is the most prevalent neurodegenerative and dementia-causing disease of our time. Multiple lines of information provided by experimental, epidemiological, neuropathological and genetic studies suggest a pathological role for innate and adaptive immune activation in this disease. Here, we review the cell types and pathological mechanisms involved in disease development as well as the influence of genetics and lifestyle factors. Given the decade-long preclinical stage of Alzheimer disease, these mechanisms and their interactions are driving forces behind the spread and progression of the disease. The identification of treatment opportunities will require a precise understanding of the cells and mechanisms involved as well as a clear definition of their temporal and topographical nature. We will also discuss new therapeutic strategies for targeting neuroinflammation, which are now entering the clinic and showing promise for patients.
PMID: 39653749
ISSN: 1474-1741
CID: 5762402
Dopamine neuron dysfunction and loss in the PrknR275W mouse model of juvenile parkinsonism
Mutations in the PRKN gene encoding the protein parkin cause autosomal recessive juvenile parkinsonism (ARJP). Harnessing this mutation to create an early-onset Parkinson's disease mouse model would provide a unique opportunity to clarify the mechanisms involved in the neurodegenerative process and lay the groundwork for the development of neuroprotective strategies. To this end, we created a knock-in mouse carrying the homozygous PrknR275W mutation, which is the missense mutation with the highest allelic frequency in PRKN patients. We evaluated the anatomical and functional integrity of the nigrostriatal dopamine (DA) pathway, as well as motor behaviour in PrknR275W mice of both sexes. We report here that PrknR275W mice show early DA neuron dysfunction, age-dependent loss of DA neurons in the substantia nigra, decreased DA content and stimulus-evoked DA release in the striatum, and progressive motor impairment. Together, these data show that the PrknR275W mouse recapitulates key features of ARJP. Thus, these studies fill a critical need in the field by introducing a promising new Parkinson's disease model in which to study causative mechanisms of the disease and test therapeutic strategies.
PMID: 39350737
ISSN: 1460-2156
CID: 5762092
AI is a viable alternative to high throughput screening: a 318-target study
High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery.
SCOPUS:85191821387
ISSN: 2045-2322
CID: 5658952
Opioid use and poisoning in hospitalized patients with chronic kidney disease
BACKGROUND:Identifying factors associated with uncomplicated and complicated opioid use is essential, especially with regard to safety concerns in impaired kidney function. Literature about opioid prescription and their potential complications in patients with different stages of chronic kidney disease (CKD) is scarce. This study describes opioid use and poisoning in hospitalized CKD patients. METHODS:The National Inpatient Database (NIS) was queried from 2016 to 2020 to identify which patients with known CKD stages were admitted with diagnoses of uncomplicated and complicated opioid use, and opioid poisoning. Patients with end-stage kidney disease receiving any form of renal replacement therapy were excluded. CKD1 served as a reference, and demographic and socio-economic characteristics were accounted for. Logistic regressions were performed to evaluate the relationship between CKD stages and each condition. RESULTS:The final cohort included 2,917,404 (14,587,017 weighted) CKD patients, of whom 1.763 ± 0.023% and 1.177 ± 0.016% had uncomplicated and complicated opioid use, respectively. Odds of uncomplicated use were lower with more advanced CKD stages. We observed an increase of complicated use with milder forms of CKD. No differences in odds of complicated opioid use were found when CKD4-5 patients were compared to CKD1. After adjustment, opioid use was found to be the main predictor of poisoning in hospitalized CKD patients. CONCLUSION/CONCLUSIONS:Prescribers appear to be more cautious in patients with advanced CKD, with lower odds of being on opioid analgesics in this group. Most CKD patients had higher odds of complicated use, and poisoning was essentially driven by complicated opioid use rather than CKD stage.
PMID: 39616593
ISSN: 1724-6059
CID: 5804232
Opportunities and challenges of single-cell and spatially resolved genomics methods for neuroscience discovery
Over the past decade, single-cell genomics technologies have allowed scalable profiling of cell-type-specific features, which has substantially increased our ability to study cellular diversity and transcriptional programs in heterogeneous tissues. Yet our understanding of mechanisms of gene regulation or the rules that govern interactions between cell types is still limited. The advent of new computational pipelines and technologies, such as single-cell epigenomics and spatially resolved transcriptomics, has created opportunities to explore two new axes of biological variation: cell-intrinsic regulation of cell states and expression programs and interactions between cells. Here, we summarize the most promising and robust technologies in these areas, discuss their strengths and limitations and discuss key computational approaches for analysis of these complex datasets. We highlight how data sharing and integration, documentation, visualization and benchmarking of results contribute to transparency, reproducibility, collaboration and democratization in neuroscience, and discuss needs and opportunities for future technology development and analysis.
PMID: 39627587
ISSN: 1546-1726
CID: 5763762
