bluuebunny/crossref_metadata_2025_split huggingface dataset:
From macro to micro: De novo genomes of Aedes mosquitoes enable comparative genomics among close and distant relatives
Authors: Morinaga Gen , Balcazar Darío , Badolo Athanase , Iyaloo Diana , Tantely Luciano , Mouillaud Theo , Sharakhova Maria , Geib Scott M. , Paupy Christophe , Ayala Diego , Powell Jeffrey R. , Gloria-Soria Andrea , Soghigian John 
Published: January 2025

AbstractThe yellow fever mosquito (Aedes aegypti) is an organism of high medical importance because it is the primary vector for diseases such as yellow fever, Zika, dengue, and chikungunya. Its medical importance has made it a subject of numerous efforts to understand their biology. One such effort, was the development of a high-quality reference genome (AaegL5). However, this reference genome was sourced from a highly inbred laboratory strain with unknown geographic origin. Thus, the reference is not representative of a wild mosquito, let alone one from its native range in sub-Saharan Africa. To better understand the genetic architecture ofAe. aegyptiand their sister species, we developed twode novochromosome-scale genomes with sequences sourced from single individuals: one ofAe. aegypti formosus(Aaf) from Burkina Faso and one ofAe. mascarensis(Am) from Mauritius. Both genomes exhibit high contiguity and gene completeness, comparable to AaegL5. While Aaf exhibits high degree of synteny to AaegL5, it also exhibits several large inversions. We further conducted comparative genomic analyses using our genomes and other publicly available culicid reference genomes to find extensive chromosomal rearrangements between major lineages. Overrepresentation analysis of expanded genes in Aaf, AaegL5, and Am revealed that while the overarching category of genes that have expanded are similar, the specific genes that have expanded differ. Our findings elucidate novel insights into chromosome evolution at both microevolutionary and macroevolutionary scales. The genomic resources we present are additions to the arsenal of biologists in understanding mosquito biology and genome evolution.SignificanceAedes aegyptiis a major arboviral disease vector found throughout the tropics and sub-tropics. Its subspecies differ ecologically, as native sub-Saharan African form feeds on mammals generally and inhabit both sylvatic and domestic areas and the global invasive form preferentially feeds on humans and lives primarily domestic areas. Their medical importance has prompted the development of a high-quality reference genome, but it was sourced from an inbred laboratory strain of unknown origin. Here, we leveraged PacBio HiFi sequencing and HiC sequencing to develop the first de novo genome ofAe. aegyptisampled its native range in Burkina Faso. We also present a de novo genome ofAe. mascarensis, its sister species. Our genomes are comparably contiguous and complete to the reference genome. Comparative genomic analysis using our genomes and other culicid reference genomes reveal extensive chromosomal rearrangements.
Assessment and staging of A/T/N with a single dynamic [18F]PI-2620 recording
Authors: Gnörich Johannes , Kusche-Palenga Julia , Kling Agnes , Dehsarvi Amir , Bronte Angela , Frontzkowski Lukas , Zatcepin Artem , Zaganjori Mirlind , Schöberl Florian , Roemer Sebastian N , Rauchmann Boris-Stephan , Kurz Carolin , Palleis Carla , Bernhardt Alexander M , Jäck Alexander , Katzdobler Sabrina , Scheifele Maximilian , Bauer Theresa , Bischof Gérard N , Eimeren Thilo van , Drzezga Alexander , Häckert Jan , Perneczky Robert , Rullmann Michael , Bürger Katharina , Zwergal Andreas , Levin Johannes , Bartenstein Peter , Sabri Osama , Barthel Henryk , Stöcklein Sophia , Höglinger Günter , Franzmeier Nicolai , Brendel Matthias 
Published: January 2025

AbstractPatients with Alzheimer’s disease (AD) and clinically overlapping neurodegenerative diseases are classified molecularly using the A/T/N classification system. Apart from fluid biomarkers and structural MRI, the three-dimensional A/T/N system incorporates characteristic features from β-amyloid-PET (A), tau-PET (T), and FDG-PET (N). We evaluated if dynamic features of tau-PET with [18F]PI-2620 allow assessment of A/T/N in individual patients using a single imaging session. Cortical tissue clearance (K2a) of [18F]PI-2620 was validated as a surrogate of the β-amyloid status against β-amyloid-PET and cerebrospinal fluid (CSF) Aβ42/40ratio, demonstrating remarkable positive (91.5%) and negative (95.1%) predictive values at an AUC of 0.99 (P<0.0001). K2a outperformed cortical tau burden as a surrogate for β-amyloid status in 47 participants with a clinical diagnosis of probable AD (3/4-repeat(R)-tauopathy) and 82 β-amyloid-negative patients with primary 4R-tauopathies. Perfusion-like [18F]PI-2620 images (R1) were validated as a surrogate marker for neuronal injury, exhibiting strong quantitative and visual correlations with FDG-PET and early-phase β-amyloid-PET, as well as with volumetric MRI and CSF total tau levels. Composite quantitative A/T/N indices facilitated personalized staging along temporal disease trajectories. Our results suggest that [18F]PI-2620 imaging has the potential to facilitate the assessment of region and stage dependent PET-based A/T/N during a single dynamic PET session.Graphical Abstract
Glymphatic defect in isolated REM sleep behavior disorder is associated with phenoconversion to Parkinson’s disease
Authors: Ayral Violette , Pastor-Bernier Alexandre , Daneault Véronique , Tremblay Christina , Filiatrault Marie , Haddad Celine , Gagnon Jean-François , Postuma Ronald , Dusek Petr , Marecek Stanislav , Varga Zsoka , Klein Johannes , Hu Michele T. , Lehéricy Stéphane , Arnulf Isabelle , Vidailhet Marie , Corvol Jean-Christophe ,   ICEBERG Study Group, Rahayel Shady ,   Quebec Parkinson Network
Published: January 2025

AbstractIsolated rapid eye movement (REM) sleep behavior disorder (iRBD) is characterized by the loss of muscle atonia and abnormal, often violent, movements and vocalizations during REM sleep. It is the strongest prodromal marker for progression to synucleinopathies such as dementia with Lewy bodies (DLB) and Parkinson’s disease (PD). iRBD individuals already show brain changes consistent with manifest synucleinopathies, but their mechanisms remain poorly understood. The glymphatic system is involved in the brain clearance of waste products and its defect has been associated with a higher likelihood of pathological burden and neurodegeneration. The presence of glymphatic system dysfunction revealed by neuroimaging in iRBD and its association with disease progression remain uninvestigated, including its potential to predict conversion toward distinct trajectories of synucleinopathies.We analyzed diffusion-weighted imaging data from a large international multicentric cohort of polysomnography-confirmed iRBD individuals and healthy controls. We used diffusion tensor imaging along the perivascular space to assess glymphatic function and derived a glymphatic index based on the diffusivity occurring within masks placed on associative and projection fibers adjacent to the lateral ventricles. The index was compared between groups and correlated with motor and cognitive features. Cox regression models assessed the relationship between glymphatic index and the likelihood of conversion to PD, DLB or remaining disease-free.Our analyses included 250 polysomnography-confirmed iRBD participants (mean age 66.5 ± 6.8 years; 87% men) and 178 controls (65.7 ± 6.8 years; 81% men). There was a significantly reduced glymphatic index in iRBD individuals compared to controls. Among the 224 iRBD individuals followed longitudinally (6.1 years, 1-16 years), 65 developed a neurodegenerative disease. iRBD converters exhibited lower glymphatic index compared to non-converters. Lower glymphatic index was associated with a higher risk of phenoconversion towards PD over time compared to remaining disease-free (hazard ratio = 2.43, 95% CI = 1.13-5.25, P = 0.012).This study reports glymphatic dysfunction in iRBD and its potential for predicting conversion to PD, underscoring its utility in identifying at-risk iRBD individuals.
NAMPT activity plays a key role in driving autoimmune processes that characterise type 1 diabetes development in mice
Authors: Egbase Daniel , Sayers Sophie R. , Haq Naila , Varghese Jithu , Bhattacharya Sreya , Kynaston Jay , Hubber Ella L. , Smith Lorna , Pullen Timothy J. , Gerdes Henry , Lee Vivian K. , Hopkins David , Zhao Minh , Cheah Yee , Greally Joshua , Butterworth Sam , Pearson James A , Bewick Gavin , Persaud Shanta , Caton Paul W. 
Published: January 2025

AbstractObjectiveType 1 diabetes (T1D) is characterised by destruction of pancreatic beta cells by islet-infiltrating cytotoxic lymphocytes, and elevated intra-islet secretion of pro-inflammatory cytokines. However, the underlying pathophysiological mechanisms remain incompletely understood. We hypothesise that abnormal elevation of islet NAD, via activation of NAMPT, plays a key role in driving islet autoimmune processes in T1D, and that conversely, NAMPT inhibition may be an attractive therapeutic approach for T1D.MethodsIslets were isolated from non-diabetic CD1 mice or obtained from human islet donors and exposed to pro-inflammatory cytokine cocktail (IL-1β, TNFα and IFNγ) +/− NAMPT inhibitor. Beta-cell function was determined by static glucose-stimulated insulin secretion. Islet apoptosis was determined by caspase 3/7 activity. Islet cell differential gene expression was assessed via bulk-RNA sequencing. Diabetes was induced in CD1 mice via multiple low dose streptozotocin (MLDS) injection. MLDS mice were then administered FK866 (10 mg/kg; IP) or saline equivalent for 16 days. Ambient blood glucose was measured every 2-3 days. Beta-cell function was assessed by measurement of serum insulin and c-peptide levels. Insulin content was assessed by flow cytometry. Intra-islet immune cell infiltration, as well as immune cell proliferation and cytokine production were assessed via flow cytometry. For migration assays, islets were isolated from BALB/c mice dispersed and reaggregated into reformed islets. CD8+cells were isolated from splenocytes derived from NY8.3 NOD mice migration of immune cells was assessed using a transwell culture protocol.ResultsNAMPT inhibition with FK866 or compound 17 protected mouse and human islets against cytokine-mediated beta cell dysfunction and death. RNAseq revealed that inhibiting NAMPT blocked pro-inflammatory cytokine-mediated gene expression linked to pro-inflammatory responses and leukocyte migration. FK866 improved glycaemic control and beta-cell function in MLDS mice. FK866 also reduced proportions of islet-residing TNFα producing CD4+T-cells and F4/80+macrophages, proliferation of spleen-derived CD4+and CD8+T-cells, and proliferation of islet-derived CD4+T-cells and F4/80+macrophages. Finally, FK866 was able to block pro-inflammatory cytokine-mediated migration of cytotoxic CD8+T-cells into reformed islets.ConclusionsThis data supports a key immunomodulatory role for NAMPT in islet autoimmunity. NAMPT inhibition may represent a novel therapeutic approach for T1D.
Linalool andtrans-nerolidol prevent pentylenetetrazole-induced seizures in adult zebrafish
Authors: Silva Amanda L. , Bastos Leonardo M. , Gallas-Lopes Matheus , Chitolina Rafael , Reis Carlos G. , Nunes Domingos Sávio , Elisabetsky Elaine , Herrmann Ana P. , Calcagnotto Maria Elisa , Piato Angelo 
Published: January 2025

ABSTRACTEthnopharmacological relevancelinalool (LIN) andtrans-nerolidol (NER) are terpene alcohols found in high concentrations in plant-derived essential oils used as a traditional treatment in many cultures. Several studies evaluating the effects of these essential oils and their isolated compounds have shown antiseizure, sedative, neuroprotective, and antioxidant properties in acute seizure models bothin vitroandin vivo. Therefore, this study aimed to evaluate the effects of acute exposure to LIN or NER on a pentylenetetrazole (PTZ)-induced seizure model in adult zebrafish (Danio rerio).Methods240 adult wild-type zebrafish were randomly allocated to the experimental groups: control (dechlorinated water), 1% DMSO (vehicle), diazepam (50 µM DZP), and LIN or NER (4, 40 and 400 µM). Animals were exposed to the treatment solution (400 mL) for 10 minutes, taken to a washout beaker (dechlorinated water, 400 mL) for 5 minutes, and recorded in the test apparatus containing 10 mM PTZ for 20 minutes. Experienced researchers conducted a blinded analysis of behavioral seizure phenotypes using BORIS® software. Additionally, locomotor activity was evaluated through ANY-Maze™ tracking software, ensuring precise and unbiased assessment of movement behaviors.Resultsthe highest concentration of LIN (400 µM) and NER (40 and 400 µM) increased the latency to reach clonic and tonic-like seizure stages while decreasing the seizure intensity. Interestingly, NER has shown a larger effect size than the positive control group DZP, and at a concentration of 40 µM, increased locomotor behavior.Conclusionour findings show the antiseizure properties of LIN and NER in zebrafish acutely exposed to PTZ, delaying the time to reach the highest seizure stages and decreasing seizure intensity. These results are consistent with previous experiments conducted in mice and amplify the external validity of these compounds, highlighting their potential as antiseizure remedy candidates.Graphical abstractCreated using BioRender.
Dementia Training for Healthcare Professionals: A Systematic Policy and Evidence Review
Authors: Zabihi Sedigheh , Delray Saskia , Muralidhar Malvika , Banerjee Sube , Giebel Clarissa , Harrison Dening Karen , Birks Yvonne , Hunter Rachael , Akhlak Rauf Mohammed , Kenten Charlotte , Walpert Madeleine , Cooper Claudia 
Published: January 2025

AbstractObjectiveTo review policies and research on the effectiveness of healthcare professionals’ dementia trainingDesignPolicy and systematic reviewSettingHealthcare servicesParticipantsHealthcare professionalsInterventionTrainingMeasurementsWe reviewed relevant English policies and searched electronic databases for primary research studies (between 2015-2024) evaluating dementia training for healthcare professionals. We assessed risk of bias using the Mixed Methods Appraisal Tool, prioritising studies scoring 4+, of interventions supported by Randomised Controlled Trial evidence, and reported outcomes using Kirkpatrick’s framework. We consulted professional stakeholders in a focus group regarding how findings might inform practice.ResultsSixteen policies and related documents highlighted concerns about the limited implementation of the Dementia Core Skills Education and Training Framework (DCSETF). We reviewed 63 primary research studies. Only one study met priority criteria; it evaluated a Train-the-Trainer (TTT), team-based reflective practice model, which improved primary care nurses’ and doctors’ learning, and self-reported practice over ≥3 months. Higher quality, controlled studies evaluated a TTT programme for hospital staff, improving client outcomes (agitation) over ≤5 days; an expert-led two-day interactive training for inpatient nurses that reduced role strain; and an expert-led, nine-week, occupational therapy-derived training programme that improved retirement community staff strategies for client activity engagement. Eight focus group attendees considered time a limiting factor to evidence implementation, but valued group training to share experiences; and TTT models to enable tailoring to local contexts.ConclusionsBy increasing reach of dementia training and embedding learning in practice, Train-the-Trainer models could increase care quality and DCSETF implementation.
Automated imaging-based tumor burden and pre-treatment circulating tumor DNA in HPV-associated oropharynx cancer
Authors: Bakhtiar Mina , Ye Zezhong , Schoenfeld Jonathan D. , Mohammadi Homan , Guenette Jeffrey P. , Rettig Eleni M. , Hanna Glenn J. , Kann Benjamin H. 
Published: January 2025

ABSTRACTBackgroundArtificial intelligence (AI)-based imaging analysis has applications for the diagnosis of head and neck malignancies, and serum circulating tumor-associated DNA (ctDNA) is an emerging biomarker being evaluated for response assessment and risk stratification in human papilloma virus (HPV)-associated oropharynx squamous cell carcinoma (HPV-OPSCC). The relationship between automated imaging biomarkers and ctDNA has not yet been explored.ObjectiveTo test the association between ctDNA and AI-derived measures of tumor burden among patients with HPV-OPSCC.Design, Setting, and ParticipantsThis cross-sectional study included patients who were treated with curative intent for HPV-OPSCC between 2020-2023, prospectively enrolled on a blood collection protocol (Clinical trials.gov identifier:NCT04965792).ExposuresClinical factors including demographics, AJCC 8thedition clinical staging, and HPV genotype.Main Outcomes and MeasuresPre-treatment serum measurement of circulating tumor-tissue modified viral (TTMV) HPV-DNA using a commercially available test, measured as a continuous value (fragments/mL). Primary tumor and nodal volumes, total tumor volume, and cystic/necrotic nodal volume were generated on pre-treatment diagnostic or radiation CT- planning scans using a prospectively validated AI auto-segmentation algorithm. Assessments of model fit: Akaike information criterion (AIC) and Bayesian information criterion (BIC).Results170 patients with HPV-OPSCC were included in the study. On univariable regression, primary tumor volume (coeff=39.43, p<0.001), nodal volume (coeff=39.54, p<0.001), AJCC 8thedition Tumor (T) stage (coeff = 1031.09, p=0.009), Nodal (N) stage (coeff=1840, p=0.018), HPV subtype 16 (coeff=3072.40, p=0.006), and CCI (coeff=-596.60, p=0.038) were associated with ctDNA. Cystic nodal volume was not associated with ctDNA (coeff=0.31, p=0.11). On multivariable analysis, primary tumor and nodal volumes were associated with ctDNA (coeff=34.79, p=0.001 and coeff=24.68, p=0.022, respectively), but T and N stage were not (coeff=-439.28, p=0.37 and coeff=238.19, p=0.29, respectively). Including automated tumor and nodal volumes improved model fit compared to T and N stage alone (3420.96 vs 3435.88 AIC, 3449.18 vs 3457.83 BIC).Conclusions and RelevanceAI-automated volumetrics on pretreatment imaging are independently associated with ctDNA, controlling for clinical stage. The association is stronger than staging and improved predictive capacity of regression models. AI-automated volumetrics may provide a practical correlate to ctDNA levels and help risk stratify patients.
LDAK-PBAT: A Pathway-Based Analysis Tool for Decoding the Genetics of Complex Diseases
Authors: Berrandou Takiy-Eddine , Speed Doug 
Published: January 2025

AbstractWe introduce LDAK-PBAT, a novel tool for detecting gene pathways associated with complex traits. LDAK-PBAT tests pathways for significance using a heritability-based framework that controls for both the contributions of genes not in the pathway and of inter-genic SNPs.LDAK-PBAT is computationally efficient, requiring only GWAS summary statistics and a reference panel, and when applied to human traits, can test 1000s of pathways within minutes. When assessed using simulated phenotypes, we find that LDAK-PBAT is well calibrated and has high sensitivity and specificity, outperforming both MAGMA and hypergeometric testing (F1 score of 0.734, versus 0.636 and 0.570, respectively).When used to test 6,000 pathways for each of 37 traits (obtained from the UK Biobank, Millions Veterans Program and psychiatric genomics consortium; sample sizes ranging from 17,014 to 1,114,458), LDAK-PBAT identified 4,861 significant pathways (P < 0.05/6000), which is substantially more than found by MAGMA (97) and hypergeometric testing (522).LDAK-PBAT emerges as a powerful tool for advancing genetic research, offering advanced insights into complex diseases. Its precise estimation of pathway enrichment and heritability, along with superior performance in detecting significant pathways. LDAK-PBAT holds significant promise for uncovering the genetic underpinnings of complex diseases and driving forward the development of personalized medicine.
Primary Aldosteronism and Long-term Outcomes Using PAMO Definition
Authors: Chu Wen-Kai , Lin Yen-Hung , Wu Vin-Cent 
Published: January 2025

AbstractBackgroundPrimary aldosteronism (PA) is the most common cause of secondary hypertension, associated with increased cardiovascular morbidity and mortality. This study evaluated biochemical and clinical responses to mineralocorticoid receptor antagonist (MRA) therapy and identified predictors of treatment success based on the Primary Aldosteronism Medical Outcomes (PAMO) consensus.MethodsThis observational study analyzed data from the TAIPAI database linked to the National Health Insurance Research Databases, including 1,305 PA patients between June 2007 and June 2021. After excluding those who underwent surgery during the study period or had relevant disease, 269 patients were classified according to their clinical and biochemical responses to MRA therapy based on the PAMO criteria.ResultsAmong the 269 patients (mean age: 54.9±11.5 years, 40.9% male), 22.3% achieved clinical success, 55.4% partial success, and 22.3% failed. Biochemically, 56.9% of patients achieved success, 37.5% partial success, and 5.6% failed. Notably, 14.1% of patients achieved both clinical and biochemical success. After a mean follow-up period of six years, clinical success was significantly associated with a reduction in major adverse cardiovascular events (p=0.020), whereas biochemical success alone did not show the same association. Cox proportional hazards analysis demonstrated a significant association between Charlson comorbidity score (HR=1.28, p=0.003), clinical success (HR=0.29, p=0.047), and cardiovascular outcomes.ConclusionsMRA therapy achieved clinical success in 22.3% and biochemical success in 56.9% of PA patients. After a mean 6 years follow-up, clinical success independently reduced MACE risk, regardless of whether biochemical success is achieved. This highlights the importance of prioritizing clinical outcomes in PA treatment.
Nuclear Speckle Dynamics are Controlled by Polyphosphate Inhibition of CLK Proteins
Authors: Lázaro Blanca , Tadeo-Masa Francisco J. , Rodriguez Andrea , Ayuso Lucia , Martínez-Láinez Joan M , Quandt Eva , Bernard Maribel , Borghi Filipy , Saiardi Adolfo , Juan-Mateu Jonàs , Jiménez Javier , Clotet Josep , Bru Samuel 
Published: January 2025

ABSTRACTNuclear speckles (NS) are membrane-less nuclear organelles that act as critical hubs for pre-mRNA splicing. Defects in splicing are linked to several human diseases, including cancer, Alzheimer’s disease, and dystrophies. While CLK kinases regulate the mobilization of splicing factors from NS, the molecular mechanisms underlying NS assembly and dissolution remain unclear. Using an adaptation of the Biotinylation by Antibody Recognition (BAR) technique, we identify polyphosphate (polyP) as a novel and essential regulator of NS dynamics. Polyphosphate, a highly conserved polyanion composed of a chain of phosphate molecules, is involved in several functions in mammalian cells. Here, we show that polyP interacts with the NS core component SRRM2, and polyP depletion disrupts NS organization releasing splicing factors into the nucleoplasm. RNA-seq analysis reveals that polyP depletion increases exon inclusion, particularly in long genes with multiple exons, highlighting its role in splicing regulation. Mechanistically, we demonstrate that polyP acts as a physiological inhibitor of CLK3 kinase, preventing the phosphorylation of SR proteins and thereby maintaining NS stability. Our findings not only expand our understanding of NS biology but also provide new insights into the polyP involvement in splicing-related diseases.GRAPHICAL ABSTRACT