bluuebunny/crossref_metadata_2025_split huggingface dataset:
TREM2 variants that cause early dementia and increase Alzheimer’s disease risk affect gene splicing
Authors: Kiianitsa Kostantin , Lukes Maria E , Hayes Brian J , Brutman Julianna N , Valdmanis Paul N , Bird Thomas D , Raskind Wendy H , Korvatska Olena 
Published: January 2024

Abstract
Loss-of-function variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are responsible for a spectrum of neurodegenerative disorders. In the homozygous state, they cause severe pathologies with early onset dementia, such as Nasu-Hakola disease and behavioural variants of frontotemporal dementia (FTD), whereas heterozygous variants increase the risk of late-onset Alzheimer’s disease (AD) and FTD. For over half of TREM2 variants found in families with recessive early onset dementia, the defect occurs at the transcript level via premature termination codons or aberrant splicing. The remaining variants are missense alterations thought to affect the protein; however, the underlying pathogenic mechanism is less clear. In this work, we tested whether these disease-associated TREM2 variants contribute to the pathology via altered splicing.
Variants scored by SpliceAI algorithm were tested by a full-size TREM2 splicing reporter assay in different cell lines. The effect of variants was quantified by qRT-/RT-PCR and western blots. Nanostring nCounter was used to measure TREM2 RNA in the brains of NHD patients who carried spliceogenic variants. Exon skipping events were analysed from brain RNA-Seq datasets available through the Accelerating Medicines Partnership for Alzheimer’s Disease Consortium.
We found that for some Nasu-Hakola disease and early onset FTD-causing variants, splicing defects were the primary cause (D134G) or likely contributor to pathogenicity (V126G and K186N). Similar but milder effects on splicing of exons 2 and 3 were demonstrated for A130V, L133L and R136W enriched in patients with dementia. Moreover, the two most frequent missense variants associated with AD/FTD risk in European and African ancestries (R62H, 1% in Caucasians and T96K, 12% in Africans) had splicing defects via excessive skipping of exon 2 and overproduction of a potentially antagonistic TREM2 protein isoform. The effect of R62H on exon 2 skipping was confirmed in three independent brain RNA-Seq datasets.
Our findings revealed an unanticipated complexity of pathogenic variation in TREM2, in which effects on post-transcriptional gene regulation and protein function often coexist. This necessitates the inclusion of computational and experimental analyses of splicing and mRNA processing for a better understanding of genetic variation in disease.
Longitudinal flortaucipir, metabolism and volume differ between phonetic and prosodic speech apraxia
Authors: Tetzloff Katerina A , Martin Peter R , Duffy Joseph R , Utianski Rene L , Clark Heather M , Botha Hugo , Machulda Mary M , Thu Pham Nha Trang , Schwarz Christopher G , Senjem Matthew L , Jack Clifford R , Lowe Val J , Josephs Keith A , Whitwell Jennifer L 
Published: January 2024

Abstract
Progressive apraxia of speech (PAOS) is a neurodegenerative motor-speech disorder that most commonly arises from a four-repeat tauopathy. Recent studies have established that progressive apraxia of speech is not a homogenous disease but rather there are distinct subtypes: the phonetic subtype is characterized by distorted sound substitutions, the prosodic subtype by slow and segmented speech and the mixed subtype by a combination of both but lack of predominance of either. There is some evidence that cross-sectional patterns of neurodegeneration differ across subtypes, although it is unknown whether longitudinal patterns of neurodegeneration differ.
We examined longitudinal patterns of atrophy on MRI, hypometabolism on 18F-fluorodeoxyglucose-PET and tau uptake on flortaucipir-PET in a large cohort of subjects with PAOS that had been followed for many years. Ninety-one subjects with PAOS (51 phonetic, 40 prosodic) were recruited by the Neurodegenerative Research Group. Of these, 54 (27 phonetic, 27 prosodic) returned for annual follow-up, with up to seven longitudinal visits (total visits analysed = 217). Volumes, metabolism and flortaucipir uptake were measured for subcortical and cortical regions, for all scans. Bayesian hierarchical models were used to model longitudinal change across imaging modalities with PAOS subtypes being compared at baseline, 4 years from baseline, and in terms of rates of change.
The phonetic group showed smaller volumes and worse metabolism in Broca’s area and the striatum at baseline and after 4 years, and faster rates of change in these regions, compared with the prosodic group. There was also evidence of faster spread of hypometabolism and flortaucipir uptake into the temporal and parietal lobes in the phonetic group. In contrast, the prosodic group showed smaller cerebellar dentate, midbrain, substantia nigra and thalamus volumes at baseline and after 4 years, as well as faster rates of atrophy, than the phonetic group. Greater hypometabolism and flortaucipir uptake were also observed in the cerebellar dentate and substantia nigra in the prosodic group. Mixed findings were observed in the supplementary motor area and precentral cortex, with no clear differences observed across phonetic and prosodic groups.
These findings support different patterns of disease spread in PAOS subtypes, with corticostriatal patterns in the phonetic subtype and brainstem and thalamic patterns in the prosodic subtype, providing insight into the pathophysiology and heterogeneity of PAOS.
The significance and limited influence of cerebrovascular reactivity on age and sex effects in task- and resting-state brain activity
Authors: Chen Donna Y , Di Xin , Yu Xin , Biswal Bharat B 
Published: January 2024

Abstract
Functional MRI measures the blood-oxygen-level dependent signals, which provide an indirect measure of neural activity mediated by neurovascular responses. Cerebrovascular reactivity affects both task-induced and resting-state blood-oxygen-level dependent activity and may confound inter-individual effects, such as those related to aging and biological sex. We examined a large dataset containing breath-holding, checkerboard, and resting-state tasks. We used the breath-holding task to measure cerebrovascular reactivity, used the checkerboard task to obtain task-based activations, and quantified resting-state activity with amplitude of low-frequency fluctuations and regional homogeneity. We hypothesized that cerebrovascular reactivity would be correlated with blood-oxygen-level dependent measures and that accounting for these correlations would result in better estimates of age and sex effects. We found that cerebrovascular reactivity was correlated with checkerboard task activations in the visual cortex and with amplitude of low-frequency fluctuations and regional homogeneity in widespread fronto-parietal regions, as well as regions with large vessels. We also found significant age and sex effects in cerebrovascular reactivity, some of which overlapped with those observed in amplitude of low-frequency fluctuations and regional homogeneity. However, correcting for the effects of cerebrovascular reactivity had very limited influence on the estimates of age and sex. Our results highlight the limitations of accounting for cerebrovascular reactivity with the current breath-holding task.
Resting heart rate causally affects the brain cortical structure: Mendelian randomization study
Authors: Zhong Yinsheng , Li Jun , Hong Yinghui , Yang Shujun , Pei Liying , Chen Xuxiang , Wu Haidong , Wang Tong 
Published: January 2024

Abstract
Resting heart rate (RHR) has been linked to impaired cortical structure in observational studies. However, the extent to which this association is potentially causal has not been determined. Using genetic data, this study aimed to reveal the causal effect of RHR on brain cortical structure. A Two-Sample Mendelian randomization (MR) analysis was conducted. Sensitivity analyses, weighted median, MR Pleiotropy residual sum and outlier, and MR-Egger regression were conducted to evaluate heterogeneity and pleiotropy. A causal relationship between RHR and cortical structures was identified by MR analysis. On the global scale, elevated RHR was found to decrease global surface area (SA; P &lt; 0.0125). On a regional scale, the elevated RHR significantly decreased the SA of pars triangularis without global weighted (P = 1.58 × 10−4) and the thickness (TH) of the paracentral with global weighted (P = 3.56 × 10−5), whereas it increased the TH of banks of the superior temporal sulcus in the presence of global weighted (P = 1.04 × 10−4). MR study provided evidence that RHR might be causally linked to brain cortical structure, which offers a different way to understand the heart–brain axis theory.
Distinct mechanisms underlying cross-modal semantic conflict and response conflict processing
Authors: Xu Honghui , Yang Guochun , Wu Haiyan , Xiao Jing , Li Qi , Liu Xun 
Published: January 2024

AbstractInterference from task-irrelevant stimuli can occur during the semantic and response processing stages. Previous studies have shown both common and distinct mechanisms underlying semantic conflict processing and response conflict processing in the visual domain. However, it remains unclear whether common and/or distinct mechanisms are involved in semantic conflict processing and response conflict processing in the cross-modal domain. Therefore, the present electroencephalography study adopted an audiovisual 2-1 mapping Stroop task to investigate whether common and/or distinct mechanisms underlie semantic conflict and response conflict. Behaviorally, significant cross-modal semantic conflict and significant cross-modal response conflict were observed. Electroencephalography results revealed that the frontal N2 amplitude and theta power increased only in the semantic conflict condition, while the parietal N450 amplitude increased only in the response conflict condition. These findings indicated that distinct neural mechanisms were involved in cross-modal semantic conflict and response conflict processing, supporting the domain-specific cognitive control mechanisms from a cross-modal multistage conflict processing perspective.
Short- and long-term neuroplasticity interact during the perceptual learning of concurrent speech
Authors: MacLean Jessica , Stirn Jack , Sisson Alexandria , Bidelman Gavin M 
Published: January 2024

Abstract
Plasticity from auditory experience shapes the brain’s encoding and perception of sound. However, whether such long-term plasticity alters the trajectory of short-term plasticity during speech processing has yet to be investigated. Here, we explored the neural mechanisms and interplay between short- and long-term neuroplasticity for rapid auditory perceptual learning of concurrent speech sounds in young, normal-hearing musicians and nonmusicians. Participants learned to identify double-vowel mixtures during ~ 45 min training sessions recorded simultaneously with high-density electroencephalography (EEG). We analyzed frequency-following responses (FFRs) and event-related potentials (ERPs) to investigate neural correlates of learning at subcortical and cortical levels, respectively. Although both groups showed rapid perceptual learning, musicians showed faster behavioral decisions than nonmusicians overall. Learning-related changes were not apparent in brainstem FFRs. However, plasticity was highly evident in cortex, where ERPs revealed unique hemispheric asymmetries between groups suggestive of different neural strategies (musicians: right hemisphere bias; nonmusicians: left hemisphere). Source reconstruction and the early (150–200 ms) time course of these effects localized learning-induced cortical plasticity to auditory-sensory brain areas. Our findings reinforce the domain-general benefits of musicianship but reveal that successful speech sound learning is driven by a critical interplay between long- and short-term mechanisms of auditory plasticity, which first emerge at a cortical level.
Time Trends in Causes of Death in People With HIV: Insights From the Swiss HIV Cohort Study
Authors: Weber M S R , Duran Ramirez J J , Hentzien M , Cavassini M , Bernasconi E , Hofmann E , Furrer H , Kovari H , Stöckle M , Schmid P , Haerry D , Braun D L , Günthard H F , Kusejko K ,   the Swiss HIV Cohort Study, Abela I , Aebi-Popp K , Anagnostopoulos A , Battegay M , Bernasconi E , Braun D L , Bucher H C , Calmy A , Cavassini M , Ciuffi A , Dollenmaier G , Egger M , Elzi L , Fehr J , Fellay J , Furrer H , Fux C A , Günthard H F , Hachfeld A , Haerry D , Hasse B , Hirsch H H , Hoffmann M , Hösli I , Huber M , Jackson-Perry D , Kahlert C R , Keiser O , Klimkait T , Kouyos R D , Kusejko K , Labhardt N , Leuzinger K , Martinez de Tejada B , Marzolini C , Metzner K J , Müller N , Nemeth J , Nicca D , Notter J , Paioni P , Pantaleo G , Perreau M , Rauch A , Salazar-Vizcaya L , Schmid P , Speck R , Stöckle M , Tarr P , Trkola A , Wandeler G , Weisser M , Yerly S 
Published: January 2024

Abstract

Background
Advancements in access to antiretroviral therapy (ART) and human immunodeficiency virus (HIV) care have led to a decline in AIDS-related deaths among people with HIV (PWH) in Switzerland. However, data on the ongoing changes in causes of death among PWH over the past 15 years are scarce.

Methods
We investigated all reported deaths in the Swiss HIV Cohort Study between 2005 and 2022. Causes of death were categorized using the Coding Causes of Death in HIV protocol. The statistical analysis included demographic stratification to identify time trends and logistic regression models to determine associated factors for the underlying cause of death.

Results
In total, 1630 deaths were reported, with 23.7% of individuals assigned female sex at birth. These deaths included 147 (9.0%) HIV/AIDS-related deaths, 373 (22.9%) due to non-AIDS, non-hepatic cancers, 166 (10.2%) liver-related deaths, and 158 (9.7%) cardiovascular-related deaths. The median age at death (interquartile range) increased from 45.0 (40.0–53.0) years in 2005–2007 to 61.0 (56.0–69.5) years in 2020–2022. HIV/AIDS- and liver-related deaths decreased, whereas deaths from non-AIDS, non-hepatic cancers increased and cardiovascular-related deaths remained relatively stable.

Conclusions
The proportionally decreasing HIV/AIDS and liver-related deaths showcase the effectiveness of ART, comprehensive HIV patient care, and interventions targeting hepatitis C virus coinfection. Future research should focus on managing cancer and cardiovascular-related conditions as the new leading causes of death among PWH. Comprehensive healthcare strategies focusing on non–AIDS-related comorbid conditions, cancer management, and sustaining liver and cardiovascular health are needed to bridge the ongoing health disparities between PWH and the general population.
Formylated Peptide Receptor-1-Mediated Gut Inflammation as a Therapeutic Target in Inflammatory Bowel Disease
Authors: McAllister Milly J , Hall Rebecca , Whelan Robert J , Fischer Lena J , Chuah Cher S , Cartlidge Peter D , Drury Broc , Rutherford Duncan G , Duffin Rodger M , Cartwright Jennifer A , Dorward David A , Rossi Adriano G , Ho Gwo-tzer 
Published: January 2024

Abstract

Background
Formylated peptide receptor (FPR)-1 is a G-coupled receptor that senses foreign bacterial and host-derived mitochondrial formylated peptides (FPs), leading to innate immune system activation.

Aim
We sought to investigate the role of FPR1-mediated inflammation and its potential as a therapeutic target in inflammatory bowel disease (IBD).

Methods
We characterized FPR1 gene and protein expression in 8 human IBD (~1000 patients) datasets with analysis on disease subtype, mucosal inflammation, and drug response. We performed in vivo dextran-sulfate sodium (DSS) colitis in C57/BL6 FPR1 knockout mice. In ex vivo studies, we studied the role of mitochondrial FPs and pharmacological blockade of FPR1 using cyclosporin H in human peripheral blood neutrophils. Finally, we assess mitochondrial FPs as a potential mechanistic biomarker in the blood and stools of patients with IBD.

Results
Detailed in silico analysis in human intestinal biopsies showed that FPR1 is highly expressed in IBD (n = 207 IBD vs 67 non-IBD controls, P &lt; .001), and highly correlated with gut inflammation in ulcerative colitis (UC) and Crohn’s disease (CD) (both P &lt; .001). FPR1 receptor is predominantly expressed in leukocytes, and we showed significantly higher FPR1+ve neutrophils in inflamed gut tissue section in IBD (17 CD and 24 UC; both P &lt; .001). Further analysis in 6 independent IBD (data available under Gene Expression Omnibus accession numbers GSE59071, GSE206285, GSE73661, GSE16879, GSE92415, and GSE235970) showed an association with active gut inflammation and treatment resistance to infliximab, ustekinumab, and vedolizumab. FPR1 gene deletion is protective in murine DSS colitis with lower gut neutrophil inflammation. In the human ex vivo neutrophil system, mitochondrial FP, nicotinamide adenine dinucleotide dehydrogenase subunit-6 (ND6) is a potent activator of neutrophils resulting in higher CD62L shedding, CD63 expression, reactive oxygen species production, and chemotactic capacity; these effects are inhibited by cyclosporin H. We screened for mitochondrial ND6 in IBD (n = 54) using ELISA and detected ND6 in stools with median values of 2.2 gg/mL (interquartile range [IQR] 0.0–4.99; range 0–53.3) but not in blood. Stool ND6 levels, however, were not significantly correlated with paired stool calprotectin, C-reactive protein, and clinical IBD activity.

Conclusions
Our data suggest that FPR1-mediated neutrophilic inflammation is a tractable target in IBD; however, further work is required to clarify the clinical utility of mitochondrial FPs as a potential mechanistic marker for future stratification.
Perilipin 1: a systematic review on its functions on lipid metabolism and atherosclerosis in mice and humans
Authors: Desgrouas Camille , Thalheim Tabea , Cerino Mathieu , Badens Catherine , Bonello-Palot Nathalie 
Published: January 2024

Abstract
The function of perilipin 1 in human metabolism was recently highlighted by the description of PLIN1 variants associated with various pathologies. These include severe familial partial lipodystrophy and early onset acute coronary syndrome. Additionally, certain variants have been reported to have a protective effect on cardiovascular diseases. The role of this protein remains controversial in mice and variant interpretation in humans is still conflicting. This literature review has two primary objectives (i) to clarify the function of the PLIN1 gene in lipid metabolism and atherosclerosis by examining functional studies performed in cells (adipocytes) and mice and (ii) to understand the impact of PLIN1 variants identified in humans based on the variant’s location within the protein and the type of variant (missense or frameshift). To achieve these objectives, we conducted an extensive analysis of the relevant literature on perilipin 1, its function in cellular models and mice, and the consequences of its mutations in humans. We also utilized bioinformatics tools and consulted the Human Genetics Cardiovascular Disease Knowledge Portal to enhance the pathogenicity assessment of PLIN1 missense variants.
Evaluation of a digital patient education programme for Chinese immigrants after a heart attack
Authors: Shi Wendan , Zhang Ling , Ghisi Gabriela L M , Panaretto Lise , Oh Paul , Gallagher Robyn 
Published: January 2024

Abstract

Aims
To evaluate a self-administered digital education resource for patients after a heart attack (adapted simplified Chinese version of Cardiac College™) on secondary prevention knowledge and health behaviour change outcomes.

Methods and results
Chinese immigrants recovering from a heart attack were recruited from cardiac rehabilitation programmes at four metropolitan tertiary hospitals. Participants provided access to Cardiac College™ (adapted simplified Chinese version), a self-learning secondary prevention virtual education resource over 4 weeks. The web-based resources include 9 booklets and 10 pre-recorded video education sessions. Assessments included health literacy, secondary prevention knowledge, self-management behaviours, self-reported physical activity, and a heart-healthy diet. Satisfaction, acceptability, and engagement were also assessed.
From 81 patients screened, 67 were recruited, and 64 (95.5%) completed the study. The participants’ mean age was 67.2 ± 8.1 years old, 81.2% were males, and the majority had no English proficiency (65.6%). Following the intervention, significant improvements were observed for secondary prevention knowledge overall and in all subdomains, with the most improvement occurring in medical, exercise, and psychological domains (P &lt; 0.001). Dietary and self-management behaviours also improved significantly (P &lt; 0.05). According to participants, the educational materials were engaging (100%), and the content was adequate (68.8%); however, 26.6% found the information overwhelming. Overall, 46.9% were highly satisfied with the resources.

Conclusion
A self-learning virtual patient-education package improved secondary prevention knowledge and self-care behaviour in Chinese immigrants after a heart attack. The culturally adapted version of Cardiac College™ offers an alternative education model where bilingual staff or translated resources are limited.
Three-dimensional intracardiac echocardiography for left atrial appendage sizing and percutaneous occlusion guidance
Authors: Della Rocca Domenico G , Magnocavallo Michele , Gianni Carola , Mohanty Sanghamitra , Al-Ahmad Amin , Bassiouny Mohamed , Denora Marialessia , La Fazia Vincenzo Mirco , Lavalle Carlo , Gallinghouse Gerald J , Santangeli Pasquale , Polselli Marco , Sarkozy Andrea , Vetta Giampaolo , Ahmed Adnan , Sanchez Javier E , Pannone Luigi , Chierchia Gian-Battista , Tschopp David R , de Asmundis Carlo , Di Biase Luigi , Lakkireddy Dhanunjaya , Burkhardt David J , Horton Rodney P , Natale Andrea 
Published: January 2024

Abstract

Aims
Left atrial appendage (LAA) imaging is critical during percutaneous occlusion procedures. 3D-intracardiac echocardiography (ICE) features direct visualization of LAA from multiple cross-sectional planes at a time. We aimed at reporting procedural success of 3D-ICE-guided LAA occlusion and the correlation between pre-procedural transoesophageal echocardiography (TEE) and intraprocedural 3D-ICE for LAA sizing.

Methods and results
Among 274 patients undergoing left atrial appendage occlusion (LAAO) with a Watchman FLX, periprocedural ICE guidance was achieved via a commercially available 2D-ICE catheter (220 patients) or a novel (NUVISION™) 3D-ICE one (54 patients). Primary endpoint was a composite of procedural success and LAA sealing at follow-up TEE. Secondary endpoint was a composite of periprocedural device recapture/resizing plus presence of leaks ≥ 3 mm at follow-up TEE. 3D-ICE measurements of maximum landing zone correlated highly with pre-procedural TEE reference values [Pearson’s: 0.94; P &lt; 0.001; bias: −0.06 (−2.39, 2.27)]. The agreement between 3D-ICE-based device selection and final device size was 96.3% vs. 79.1% with 2D-ICE (P = 0.005). The incidence of the primary endpoint was 98.1% with 3D-ICE and 97.3% with 2D-ICE (P = 0.99). 2D-ICE patients had a trend towards a higher incidence of periprocedural device recapture/redeployment (31.5% vs. 44.5%; P = 0.09). The secondary endpoint occurred in 31.5% of 3D-ICE patients vs. 45.9% of 2D-ICE ones (P = 0.065).

Conclusion
Intracardiac echocardiography-guided LAAO showed a very high success, with no major adverse events. A very high level of agreement for LAA sizing was found between pre-procedural TEE and periprocedural 3D-ICE. 3D-ICE performed significantly better than 2D-ICE for FLX size selection and may provide better guidance during device deployment.