bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical, genomic, and neurophysiological correlates of lifetime suicide attempts among individuals with an alcohol use disorder
Authors: Barr Peter B. , Neale Zoe , Chatzinakos Chris , Schulman Jessica , Mullins Niamh , Zhang Jian , Chorlian David B. , Kamarajan Chella , Kinreich Sivan , Pandey Ashwini K. , Pandey Gayathri , de Viteri Stacey Saenz , Acion Laura , Bauer Lance , Bucholz Kathleen K. , Chan Grace , Dick Danielle M. , Edenberg Howard J. , Foroud Tatiana , Goate Alison , Hesselbrock Victor , Johnson Emma C. , Kramer John , Lai Dongbing , Plawecki Martin H. , Salvatore Jessica E. , Wetherill Leah , Agrawal Arpana , Porjesz Bernice , Meyers Jacquelyn L. 
Published: April 2023

AbstractResearch has identified clinical, genomic, and neurophysiological markers associated with suicide attempts (SA) among individuals with psychiatric illness. However, there is limited research among those with an alcohol use disorder (AUD), despite their disproportionately higher rates of SA. We examined lifetime SA in 4,068 individuals with DSM-IV alcohol dependence from the Collaborative Study on the Genetics of Alcoholism (23% lifetime suicide attempt; 53% female; mean age: 38). Within participants with an AUD diagnosis, we explored risk across other clinical conditions, polygenic scores (PGS) for comorbid psychiatric problems, and neurocognitive functioning for lifetime suicide attempt. Participants with an AUD who had attempted suicide had greater rates of trauma exposure, major depressive disorder, post-traumatic stress disorder, and other substance use disorders compared to those who had not attempted suicide. Polygenic scores for suicide attempt, depression, and PTSD were associated with reporting a suicide attempt (ORs = 1.22 – 1.44). Participants who reported a SA also had decreased right hemispheric frontal-parietal theta and decreased interhemispheric temporal-parietal alpha electroencephalogram resting-state coherences relative to those who did not, but differences were small. Overall, individuals with an AUD who report a lifetime suicide attempt appear to experience greater levels of trauma, have more severe comorbidities, and carry polygenic risk for a variety of psychiatric problems. Our results demonstrate the need to further investigate suicide attempts in the presence of substance use disorders.
Deep Learning Utilizing Suboptimal Spirometry Data to Improve Lung Function and Mortality Prediction in the UK Biobank
Authors: Hill Davin , Torop Max , Masoomi Aria , Castaldi Peter J. , Silverman Edwin K. , Bodduluri Sandeep , Bhatt Surya P. , Yun Taedong , McLean Cory Y. , Hormozdiari Farhad , Dy Jennifer , Cho Michael H. , Hobbs Brian D. 
Published: April 2023

AbstractBackgroundSpirometry measures lung function by selecting the best of multiple efforts meeting pre-specified quality control (QC), and reporting two key metrics: forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC). We hypothesize that discarded submaximal and QC-failing data meaningfully contribute to the prediction of airflow obstruction and all-cause mortality.MethodsWe evaluated volume-time spirometry data from the UK Biobank. We identified “best” spirometry efforts as those passing QC with the maximum FVC. “Discarded” efforts were either submaximal or failed QC. To create a combined representation of lung function we implemented a contrastive learning approach,Spirogram-basedContrastiveLearningFramework (Spiro-CLF), which utilized all recorded volume-time curves per participant and applied different transformations (e.g. flow-volume, flow-time). In a held-out 20% testing subset we applied the Spiro-CLF representation of a participant’s overall lung function to 1) binary predictions of FEV1/FVC < 0.7 and FEV1Percent Predicted (FEV1PP) < 80%, indicative of airflow obstruction, and 2) Cox regression for all-cause mortality.FindingsWe included 940,705 volume-time curves from 352,684 UK Biobank participants with 2-3 spirometry efforts per individual (66.7% with 3 efforts) and at least one QC-passing spirometry effort. Of all spirometry efforts, 24.1% failed QC and 37.5% were submaximal. Spiro-CLF prediction of FEV1/FVC < 0.7 utilizing discarded spirometry efforts had an Area under the Receiver Operating Characteristics (AUROC) of 0.981 (0.863 for FEV1PP prediction). Incorporating discarded spirometry efforts in all-cause mortality prediction was associated with a concordance index (c-index) of 0.654, which exceeded the c-indices from FEV1(0.590), FVC (0.559), or FEV1/FVC (0.599) from each participant’s single best effort.InterpretationA contrastive learning model using raw spirometry curves can accurately predict lung function using submaximal and QC-failing efforts. This model also has superior prediction of all-cause mortality compared to standard lung function measurements.FundingMHC is supported by NIH R01HL137927, R01HL135142, HL147148, and HL089856.BDH is supported by NIH K08HL136928, U01 HL089856, and an Alpha-1 Foundation Research Grant.DH is supported by NIH 2T32HL007427-41EKS is supported by NIH R01 HL152728, R01 HL147148, U01 HL089856, R01 HL133135, P01 HL132825, and P01 HL114501.PJC is supported by NIH R01HL124233 and R01HL147326.SPB is supported by NIH R01HL151421 and UH3HL155806.TY, FH, and CYM are employees of Google LLC
Association between Non-Dietary Cardiovascular Health and Expenditures Related to Acute Coronary Syndrome in the US between 2008–2018
Authors: Enyeji Abraham , Barengo Noël C. , Ibrahimou Boubakari , Ramirez Gilbert , Arrieta Alejandro 
Published: April 2023

AbstractBackgroundAcute Coronary Syndrome (ACS) causes the most deaths in the United States and accounts for the highest amount of healthcare spending. Cardiovascular Health (CVH) metrics have been widely used in primary prevention, but their benefits in secondary prevention on total healthcare expenditures related to ACS are largely unknown. This study aims to quantify the potential significance of ideal CVH scores as a tool in secondary cardiovascular disease prevention.MethodsIn a cross-sectional analytical study, ten years of Medical Expenditure Panel Survey (MEPS) data from 2008 to 2018 were pooled, comparing ACS to non-ACS subgroups, utilizing a Two-part model with log link and gamma distribution, since our sample had both positive and zero costs. Conditional on positive expenditure, healthcare expenditure amounts were measured as a function of ACS status, socio-demographics, and CVH while controlling for relevant covariates. Finally, interactions of ACS with CVH metrics and other key variables were included to allow for variations in the effect of these variables on the two subgroups.ResultsImprovements in CVH scores tended to reduce annual expenditures to a greater degree percentage-wise among ACS subjects compared to non-ACS groups, even though subjects with an ACS diagnosis tended to have approximately twice as big expenditures as similar subjects without an ACS diagnosis. Meanwhile, the financial impact of an ACS event on total expenditure would be approximately $88,500 ([95% CI, $70,200–106,900;p< 0.001]), and a unit improvement in CVH management score would generate savings of approximately $4160 ([95% CI, $5390–2950;p< 0.001]) in total health expenditures.ConclusionEffective secondary preventive measures through targeted behavioral endeavors and improved health factors, especially the normalization of hypertension, diabetes mellitus, body mass index, and smoking cessation, have the potential to reduce medical spending for ACS subgroups.
Solid-Phase Extraction and Enhanced Amplification-Free Detection of Pathogens Integrated by Dual-Functional CRISPR-Cas12a
Authors: Tian Zimu , Yan He , Zeng Yong 
Published: April 2023

AbstractPublic healthcare demands effective and pragmatic diagnostic tools to address the escalating challenges in infection management in resource-limited areas. Recent advance in CRISPR-based biosensing promises the development of next-generation tools for disease diagnostics, including point-of-care (POC) testing for infectious diseases. Currently prevailing strategy of developing CRISPR assays exploits only the non-specific trans-cleavage function of a CRISPR-Cas12a/Cas13a system for detection and combines it with an additional pre-amplification reaction to enhance the sensitivity. In contrast to this single-function strategy, here we present a new approach that collaboratively integrates the dual functions of CRISPR-Cas12a: sequence-specific binding and trans-cleavage activity. With this approach, we developed a POC nucleic acid assay termed Solid-Phase Extraction and Enhanced Detection assay Integrated by CRISPR-Cas12a (SPEEDi-CRISPR) that negates the need for preamplification but significantly improves the detection of limit (LOD) from the pM to fM level. Specifically, using Cas12a-coated magnetic beads, this assay combines efficient solid-phase extraction and enrichment of DNA targets enabled by the sequence-specific affinity of CRISPR-Cas12a with the fluorogenic detection by the activated Cas12a on beads. Our proof-of-concept study demonstrated that the SPEEDi-CRISPR assay affords an improved detection sensitivity for human papillomavirus (HPV)-18 with a LOD of 2.3 fM and excellent specificity to discriminate HPV-18 from HPV-16, Parvovirus B19, and scramble HPV-18. Furthermore, this robust assay was readily coupled with a portable smartphone-based fluorescence detector and a lateral flow assay for quantitative detection and visualized readout, respectively. Overall, these results should suggest that our dual-function strategy could pave a new way for developing the next-generation CRISPR diagnostics and that the SPEEDi-CRISPR assay provides a potentially useful tool for point-of-care testing.
Unsupervised representation learning improves genomic discovery and risk prediction for respiratory and circulatory functions and diseases
Authors: Yun Taedong , Cosentino Justin , Behsaz Babak , McCaw Zachary R. , Hill Davin , Luben Robert , Lai Dongbing , Bates John , Yang Howard , Schwantes-An Tae-Hwi , Zhou Yuchen , Khawaja Anthony P. , Carroll Andrew , Hobbs Brian D. , Cho Michael H. , McLean Cory Y. , Hormozdiari Farhad 
Published: April 2023

AbstractHigh-dimensional clinical data are becoming more accessible in biobank-scale datasets. However, effectively utilizing high-dimensional clinical data for genetic discovery remains challenging. Here we introduce a general deep learning-based framework, REpresentation learning for Genetic discovery on Low-dimensional Embeddings (REGLE), for discovering associations between genetic variants and high-dimensional clinical data. REGLE uses convolutional variational autoencoders to compute anon-linear, low-dimensional, disentangled embeddingof the data with highly heritable individual components. REGLE can incorporate expert-defined or clinical features and provides a framework to create accurate disease-specific polygenic risk scores (PRS) in datasets which have minimal expert phenotyping. We apply REGLE to both respiratory and circulatory systems: spirograms which measure lung function and photoplethysmograms (PPG) which measure blood volume changes. Genome-wide association studies on REGLE embeddings identify more genome-wide significant loci than existing methods and replicate known loci for both spirograms and PPG, demonstrating the generality of the framework. Furthermore, these embeddings are associated with overall survival. Finally, we construct a set of PRSs that improve predictive performance of asthma, chronic obstructive pulmonary disease, hypertension, and systolic blood pressure in multiple biobanks. Thus, REGLE embeddings can quantify clinically relevant features that are not currently captured in a standardized or automated way.
Altered Functional Networks during Gain Anticipation in Fibromyalgia
Authors: Park Su Hyoun , Michael Andrew M. , Baker Anne K. , Lei Carina , Martucci Katherine T. 
Published: April 2023

AbstractReward motivation is essential in shaping human behavior and cognition. Previous studies have shown altered reward motivation and reward brain circuitry in chronic pain conditions, including fibromyalgia. Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain, fatigue, cognitive problems, and mood-related symptoms. In this study, we analyzed brain reward networks in patients with fibromyalgia by using a data-driven approach with task-based fMRI data. fMRI data from 24 patients with fibromyalgia and 24 healthy controls were acquired while subjects performed a monetary incentive delay (MID) reward task. Functional networks were derived using independent component analysis (ICA) focused on the gain anticipation phase of the reward task. Functional activity in the motor, value-driven attention, and basal ganglia networks was evaluated during gain anticipation in both patient and healthy control groups. Compared to controls, the motor network was more engaged during gain anticipation in patients with fibromyalgia. Our findings suggest that reward motivation may lead to hyperactivity in the motor network, possibly related to altered motor processing, such as restricted movement or dysregulated motor planning in fibromyalgia. As an exploratory analysis, we compared levels of motor network engagement during early and late timepoints of the gain anticipation phase. Both groups showed greater motor network engagement during the late timepoint (i.e., closer to response), which reflected motor preparation prior to target response. Importantly, compared to controls and consistent with the initial findings described above, patients exhibited greater engagement of the motor network during both early and late timepoints. In summary, by using a novel data-driven ICA approach to analyze task-based fMRI data, we identified elevated motor network engagement during gain anticipation in fibromyalgia.
Language experience shapes predictive coding of rhythmic sound sequences
Authors: Morucci Piermatteo , Nara Sanjeev , Lizarazu Mikel , Martin Clara , Molinaro Nicola 
Published: April 2023

ABSTRACTPerceptual systems heavily rely on prior knowledge and predictions to make sense of the environment. Predictions can originate from multiple sources of information, including contextual short-term priors, based on isolated temporal situations, and context-independent long-term priors, arising from extended exposure to statistical regularities. While the effects of short-term predictions on auditory perception have been well-documented, how long-term predictions shape early auditory processing is poorly understood. To address this, we recorded magnetoencephalography data from native speakers of two languages with different word orders (Spanish: functor-initial versus Basque: functor-final) listening to simple sequences of binary sounds alternating in duration with occasional omissions. We hypothesized that, together with contextual transition probabilities, the auditory system uses the characteristic prosodic cues (duration) associated with the native language’s word order as an internal model to generate long-term predictions about incoming non-linguistic sounds. Consistent with our hypothesis, we found that the amplitude of the mismatch negativity elicited by sound omissions varied orthogonally depending on the speaker’s linguistic background and was most pronounced in the left auditory cortex. Importantly, listening to binary sounds alternating in pitch instead of duration did not yield group differences, confirming that the above results were driven by the hypothesized long-term “duration” prior. These findings show that experience with a given language can shape a fundamental aspect of human perception – the neural processing of rhythmic sounds – and provides direct evidence for a long-term predictive coding system in the auditory cortex that uses auditory schemes learned over a lifetime to process incoming sound sequences.
Long-Run Olfactory Enrichment Promotes Non-Olfactory Cognition, Noradrenergic Plasticity And Remodeling Of Brain Functional Connectivity In Aged Mice
Authors: Terrier Claire , Greco-Vuilloud Juliette , Cavelius Matthias , Thévenet Marc , Mandairon Nathalie , Didier Anne , Richard Marion 
Published: April 2023

ABSTRACTNormal brain aging is accompanied by functional and structural changes, leading to cognitive decline. A high level of cognitive stimulation during life is associated with improved cognitive performances in elderly, forming the so-called cognitive reserve whose cellular mechanisms remain largely unknown. Noradrenaline has been proposed as a molecular link between environmental stimulation and the constitution of the cognitive reserve. Taking advantage of the ability of olfactory stimulation to trigger noradrenaline release, we used repeated olfactory enrichment sessions distributed over the mouse lifespan to enable the cognitive reserve buildup. Mice submitted to lifelong olfactory enrichment whether started in early or late adulthood, displayed improved olfactory discrimination at late ages. Interestingly, benefits extended to spatial memory and cognitive flexibility and olfactory and non-olfactory cognitive performances correlated with increased noradrenergic innervation in the olfactory bulb and dorsal hippocampus. Finally, using c-Fos mapping and connectivity analysis, we reported task-specific remodeling of functional neural networks in aged mice with increased network specialization or enlargement in an olfactory discrimination or a spatial memory task respectively. We thus propose long-run olfactory enrichment as a mouse model of the cognitive reserve buildup relying on plasticity of the noradrenergic system and network remodeling to promote better cognitive aging.
Cholinergic activation of corticofugal circuits in the adult mouse prefrontal cortex
Authors: Gulledge Allan T. 
Published: April 2023

SummaryIn layer 5 of the neocortex, ACh promotes cortical output to the thalamus and brainstem by preferentially enhancing the postsynaptic excitability of pyramidal tract (PT) neurons relative to neighboring intratelencephalic (IT) neurons. Less is known about how ACh regulates the excitatory synaptic drive of IT and PT neurons. To address this question, spontaneous excitatory postsynaptic potentials (sEPSPs) were recorded in pairs of IT and PT neurons in slices of prelimbic cortex from adult female and male mice. ACh (20 µM) enhanced sEPSP amplitudes, frequencies, rise-times, and half-widths preferentially in PT neurons. These effects were blocked by the muscarinic acetylcholine receptor antagonist atropine (1 µM). When challenged with pirenzepine (1 µM), an antagonist selective for M1-type muscarinic receptors, ACh instead reduced sEPSP frequencies. The cholinergic increase in sEPSP amplitudes and frequencies in PT neurons was not sensitive to blockade of GABAergic receptors with gabazine (10 µM) and CGP52432 (2.5 µM), but was blocked by tetrodotoxin (1 µM), suggesting that ACh enhances action-potential-dependent excitatory synaptic transmission in PT neurons. ACh also preferentially promoted the occurrence of synchronous sEPSPs in pairs of PT neurons relative to IT-PT and IT-IT pairs. Finally, selective chemogenetic silencing of hM4Di-expressing PT, but not IT, neurons with clozapine-N-oxide (5 µM) blocked cholinergic enhancement of sEPSP amplitudes and frequencies in PT neurons. These data suggest that, in addition to enhancing the postsynaptic excitability of PT neurons, M1 receptor activation promotes corticofugal output by preferentially amplifying recurrent excitation within networks of PT neurons.
Prospective role of PAK6 and 14-3-3γ as biomarkers for Parkinson’s disease
Authors: Giusto Elena , Maistrello Lorenza , Iannotta Lucia , Giusti Veronica , Iovino Ludovica , Bandopadhyay Rina , Antonini Angelo , Bubacco Luigi , Barresi Rita , Plotegher Nicoletta , Greggio Elisa , Civiero Laura 
Published: April 2023

2.AbstractBackgroundParkinson’s disease is a progressive neurodegenerative disorder mainly distinguished by sporadic aetiology, although a genetic component is also well established. Variants in theLRRK2gene are associated with both familiar and sporadic disease. We have previously shown that PAK6 and 14-3-3γ protein interact with and regulate the activity of LRRK2.ObjectivesThe aim of this study is to quantify PAK6 and 14-3-3γ in plasma as a reliable biomarker strategy for the diagnosis of both sporadic and LRRK2-linked Parkinson’s disease.MethodsAfter an initial quantification of PAK6 and 14-3-3γ expression by means of Western blot in post-mortem human brains, we verified the presence of the two proteins in plasma by using quantitative ELISA tests. We analysed samples obtained from 39 healthy subjects, 40 patients with sporadic Parkinson’s disease, 50 LRRK2-G2019S non-manifesting carriers and 31 patients with LRRK2-G2019S Parkinson’s disease.ResultsThe amount of PAK6 and 14-3-3γ is significantly different in patients with Parkinson’s disease compared to healthy subjects. Moreover, the amount of PAK6 also varies with the presence of the G2019S mutation in the LRRK2 gene. Although the generalized linear models show a low association between the presence of PD and PAK6, the kinase can be added in a broader panel of biomarkers for the diagnosis of Parkinson’s disease.ConclusionsChanges of PAK6 and 14-3-3γ amount in plasma represent a shared readout for patients affected by sporadic and LRRK2-linked Parkinson’s disease. Overall, they can contribute to the establishment of an extended panel of biomarkers for the diagnosis of Parkinson’s disease.
Behavioral strategy shapes activation of the Vip-Sst disinhibitory circuit in visual cortex
Authors: Piet Alex , Ponvert Nick , Ollerenshaw Douglas , Garrett Marina , Groblewski Peter A. , Olsen Shawn , Koch Christof , Arkhipov Anton 
Published: April 2023

AbstractIn complex environments, animals can adopt diverse strategies to find rewards. How distinct strategies differentially engage brain circuits is not well understood. Here we investigate this question, focusing on the cortical Vip-Sst disinhibitory circuit. We characterize the behavioral strategies used by mice during a visual change detection task. Using a dynamic logistic regression model we find individual mice use mixtures of a visual comparison strategy and a statistical timing strategy. Separately, mice also have periods of task engagement and disengagement. Two-photon calcium imaging shows large strategy dependent differences in neural activity in excitatory, Sst inhibitory, and Vip inhibitory cells in response to both image changes and image omissions. In contrast, task engagement has limited effects on neural population activity. We find the diversity of neural correlates of strategy can be understood parsimoniously as increased activation of the Vip-Sst disinhibitory circuit during the visual comparison strategy which facilitates task appropriate responses.
Repeated MRI scans of the human brain: diurnal oscillations in healthy adults and bipolar disorder patients
Authors: Carlucci Matthew , Lett Tristram , Chavez Sofia , Malinowski Alexandra , Lobaugh Nancy J. , Petronis Art 
Published: April 2023

AbstractRegulation of biological processes according to a 24-hr rhythm is essential for the normal functioning of an organism. Temporal variation in brain MRI data has often been attributed to circadian or diurnal oscillations; however, it is not clear if such oscillations exist. We provide the first evidence that diurnal oscillations indeed govern multiple MRI metrics. We recorded cerebral blood flow, diffusion-tensor metrics, T1 relaxation, and cortical structural features every three hours over a 24-hr period in each of 16 male controls and eight male bipolar disorder patients. Diurnal oscillations were detected in numerous MRI metrics at the whole-brain level, and regionally. Rhythmicity parameters in the bipolar disorder patients were similar to the controls for most metrics, except for a larger phase variation in cerebral blood flow. The ubiquitous nature of diurnal oscillations has broad implications for neuroimaging studies and furthers our understanding of the dynamic nature of the human brain.