bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative study of enriched dopaminergic neurons from siblings with Gaucher disease discordant for parkinsonism
Authors: Hertz Ellen , Perez Gani , Hao Ying , Rytel Krystyna , Ma Charis , Kirby Martha , Anderson Stacie , Wincovitch Stephen , Andersh Kate , Ahfeldt Tim , Blanchard Joel , Qi Yue Andy , Lopez Grisel , Tayebi Nahid , Sidransky Ellen , Chen Yu 
Published: February 2024

AbstractInducible pluripotent stem cells (iPSCs) derived from patient samples have significantly enhanced our ability to model neurological diseases. Comparative studies of dopaminergic (DA) neurons differentiated from iPSCs derived from siblings with Gaucher disease discordant for parkinsonism provides a valuable avenue to explore genetic modifiers contributing toGBA1-associated parkinsonism in disease-relevant cells. However, such studies are often complicated by the inherent heterogeneity in differentiation efficiency among iPSC lines derived from different individuals. To address this technical challenge, we devised a selection strategy to enrich dopaminergic (DA) neurons expressing tyrosine hydroxylase (TH). A neomycin resistance gene(neo)was inserted at the C-terminus of theTHgene following a T2A self-cleavage peptide, placing its expression under the control of theTHpromoter. This allows for TH+ DA neuron enrichment through geneticin selection. This method enabled us to generate comparable, high-purity DA neuron cultures from iPSC lines derived from three sisters that we followed for over a decade: one sibling is a healthy individual, and the other two have Gaucher disease (GD) withGBA1genotype N370S/c.203delC+R257X (p.N409S/c.203delC+p.R296X). Notably, the younger sister with GD later developed Parkinson disease (PD). A comprehensive analysis of these high-purity DA neurons revealed that although GD DA neurons exhibited decreased levels of glucocerebrosidase (GCase), there was no substantial difference in GCase protein levels or lipid substrate accumulation between DA neurons from the GD and GD/PD sisters, suggesting that the PD discordance is related to of other genetic modifiers.
Factors influencing the implementation of integrated screening for HIV, syphilis, and hepatitis B for pregnant women in Nepal: a qualitative study
Authors: Sabin Lucie , Haghparast-Bidgoli Hassan , Thapaliya Bibhu , Chand Obindra , Bhattarai Sanju , Arjyal Abriti , Saville Naomi 
Published: February 2024

AbstractAccording to the Nepalese national guidelines, integrated screening for HIV, syphilis and hepatitis B should be offered free of charge to all pregnant women during their first antenatal visit. However, the screening uptake among pregnant women remains low in the country. Identifying factors influencing the implementation of integrated screening for HIV, syphilis, and hepatitis B is essential to increase uptake and prevent mother-to-child transmission. This study investigated the knowledge, attitude, and perceptions of pregnant women, their family members, healthcare workers and decision-makers on integrated antenatal screening. On the demand side, we conducted 26 semi-structured in-depth interviews with pregnant women, their husbands, and mothers-in-law in Kapilvastu and Kathmandu. On the supply side, we conducted 11 interviews with health workers involved in antenatal screening and local and national health system decision-makers. Data were analysed using a thematic content analysis. A combination of the social-ecological model and the WHO building blocks provided a theoretical framework for interpreting the data. The analysis showed that integrated antenatal screening for HIV, syphilis and hepatitis B in Nepal involved many stakeholders and was influenced by various factors. Barriers were mainly on the supply side, including a lack of resources, a shortage of healthcare workers and a lack of training. Husbands and in-laws also play an important role in the acceptance of screening by pregnant women, mainly in rural areas. Stigma and discrimination against people with sexually transmitted diseases were reported high in the communities, and knowledge of hepatitis B and syphilis was low. Improving integrated antenatal screening will require a multi-sectoral approach with greater engagement with communities through awareness programs and enhancement of the role of health posts. This study may be useful to inform decision-makers about the challenges and enable affecting integrated screening, to guide the design of targeted interventions to improve antenatal screening rates.
Flexible and high-throughput simultaneous profiling of gene expression and chromatin accessibility in single cells
Authors: Soltys Volker , Peters Moritz , Su Dingwen , Kučka Marek , Chan Yingguang Frank 
Published: February 2024

AbstractGene regulation consists of several highly interconnected layers including gene expression and chromatin accessibility. To understand cell-type specific regulatory circuits, both of these processes therefore need to be profiled simultaneously at single-cell level. However, these joint measurements are challenging and current methodologies suffer from limited applicability. Here, we present easySHARE-seq, an elaboration of SHARE-seq, for the simultaneous measurement of ATAC- and RNA-seq in single cells. By streamlining the barcode design, easySHARE-seq libraries have a usable sequence of up to 300bp (+200%), making it suitable for e.g. investigation of allele-specific signals or variant discovery. Furthermore, easySHARE-seq libraries do not require a dedicated sequencing run thus saving costs. Lastly, recovery of transcripts per cell is substantially boosted (> +50%) while retaining high scalability and low cost. To showcase these changes, we generated joint profiles for 19,664 murine liver nuclei, identified cell types, exploited the multi-omic measurements to linkcis-regulatory elements to their target genes and investigated liver-specific micro-scale changes. easySHARE-seq produces high-quality multiomic data sets and is applicable to a wide range of study designs.
Ontogenetic variation in the marine foraging of Atlantic salmon functionally links genomic diversity with a major life history polymorphism
Authors: Aykanat Tutku , Jacobsen Jan Arge , Hindar Kjetil 
Published: February 2024

AbstractThe ecological role of heritable phenotypic variation in free-living populations remains largely unknown. Knowledge of the genetic basis of functional ecological processes can link genomic and phenotypic diversity, providing insight into polymorphism evolution and how populations respond to environmental changes. By quantifying the marine diet of Atlantic salmon, we assessed how foraging behavior changes along the ontogeny, and in relation to genetic variation in two loci with major effects on age at maturity (six6andvgll3). We used a two-component, zero-inflated negative binomial model to simultaneously quantify foraging frequency and foraging outcome, separately for fish and crustaceans diets. We found that older salmon forage for both prey types more actively (as evidenced by increased foraging frequency), but with a decreased efficiency (as evidenced by fewer prey in the diet), suggesting an age-dependent shift in foraging dynamics. Thevgll3locus was linked to age-dependent changes in foraging behavior: younger salmon withvgll3LL(the genotype associated with late maturation) tended to forage crustaceans more often than those withvgll3EE(the genotype associated with early maturation), whereas the pattern was reversed in older salmon.Vgll3LLgenotype was also linked to a marginal increase in fish acquisition, especially in younger salmon, whilesix6was not a factor explaining the diet variation. Our results suggest a functional role for marine feeding behavior linking genomic diversity atvgll3with age at maturity among salmon, with potential age-dependent trade-offs maintaining the genetic variation. A shared genetic basis between dietary ecology and age at maturity likely subjects Atlantic salmon populations to evolution induced by bottom-up changes in marine productivity.
Stochastic cell-intrinsic stem cell decisions control colony growth in planarians
Authors: Frankovits Tamar , Cherian Prakash Varkey , Yesharim Yarden , Dobler Simon , Wurtzel Omri 
Published: February 2024

AbstractStem cells contribute to organismal homeostasis by balancing division, self-renewal and differentiation. Elucidating the strategies by which stem cells achieve this balance is critical for understanding homeostasis, and for addressing pathogenesis associated with the disruption of this balance (e.g., cancer). Planarians, highly regenerative flatworms, use pluripotent stem cells called neoblasts to maintain and regrow organs. A single neoblast can rescue an entire animal depleted from stem cells and regenerate all cell lineages. How neoblast differentiation and clonal expansion are governed to produce all the required cell types is unclear. Here, we integrated experimental and computational approaches to develop a quantitative model revealing basic principles of clonal growth of individual neoblasts. By experimentally suppressing differentiation to major lineages, we elucidated the interplay between colony growth and lineage decisions. Our findings suggest that neoblasts select their progenitor lineage based on a cell-intrinsic fate distribution. Arresting differentiation into specific lineages disrupts neoblast proliferative capacity without inducing compensatory expression of other lineages. Our analysis of neoblast colonies is consistent with a cell-intrinsic decision model that can operate without memory or communication between neoblasts. This simple cell fate decision process breaks down in homeostasis, likely because of the activity of feedback mechanisms. Our findings uncover essential principles of stem cell regulation in planarians, which are distinct from those observed in many vertebrate models. These mechanisms enable robust production of diverse cell types and facilitate regeneration of missing tissues.
T6SS-associated Rhs toxin containers: Structural and functional insights into bacterial weaponry and self-protection
Authors: Kielkopf Claudia S. , Shneider Mikhail M. , Leiman Petr G. , Taylor Nicholas M.I. 
Published: February 2024

AbstractBacteria use the type VI secretion system (T6SS) to secrete a variety of toxins into pro- and eukaryotic cells via a machinery consisting of a contractile sheath and a rigid tube. Rearrangement hotspot (Rhs) proteins represent one of the most common T6SS-secreted effectors. The C-terminal toxin domain of Rhs proteins displays great functional diversity, while the large Rhs core is characterised by YD repeats. T6SS- associated Rhs proteins are attached to the VgrG spike protein, often via an N- terminal PAAR-repeat domain. Using X-ray crystallography, we here elucidate the Rhs core structures of PAAR- and VgrG-linked Rhs proteins fromSalmonella bongoriandAdvenella mimigardefordensis, respectively. The Rhs core forms a large container made up of β-sheets that has a negatively charged interior and encloses a large volume. The presence of the toxin domain ofS. bongoriPAAR-linked Rhs does not lead to ordered density in the Rhs container, suggesting the toxin domain is at least partially unfolded. Together with bioinformatics analysis showing that Rhs toxins predominantly act intracellularly, this suggests that the Rhs core domain functions two-fold, as safety feature for the producer cell and as delivery mechanism for the toxin domain. Our results strengthen our knowledge of Rhs structure and function.
Astrocytic RNA editing regulates the host immune response to alpha-synuclein
Authors: D’Sa Karishma , Choi Minee L. , Wagen Aaron Z. , Setó-Salvia Núria , Kopach Olga , Evans James R. , Rodrigues Margarida , Lopez-Garcia Patricia , Lachica Joanne , Clarke Benjamin E. , Singh Jaijeet , Ghareeb Ali , Bayne James , Grant-Peters Melissa , Garcia-Ruiz Sonia , Chen Zhongbo , Rodriques Samuel , Athauda Dilan , Gustavsson Emil K. , Taliun Sarah A. Gagliano , Toomey Christina , Reynolds Regina H. , Young George , Strohbuecker Stephanie , Warner Tom , Rusakov Dmitri A. , Patani Rickie , Bryant Clare , Klenerman David A. , Gandhi Sonia , Ryten Mina 
Published: February 2024

AbstractRNA editing is a post transcriptional mechanism that targets changes in RNA transcripts to modulate innate immune responses. We report the role of astrocyte specific, ADAR1 mediated RNA editing in neuroinflammation in Parkinson’s disease. We generated hiPSC-derived astrocytes, neurons and co-cultures and exposed them to small soluble alpha-synuclein aggregates. Oligomeric alpha-synuclein triggered an inflammatory glial state associated with TLR activation, viral responses, and cytokine secretion. This reactive state resulted in loss of neurosupportive functions, and the induction of neuronal toxicity. Notably, interferon response pathways were activated leading to upregulation, and isoform switching of the RNA deaminase enzyme, ADAR1. ADAR1 mediates A-to-I RNA editing, and increases in RNA editing were observed in inflammatory pathways in cells, as well as in post-mortem human PD brain. Aberrant, or dysregulated, ADAR1 responses and RNA editing may lead to sustained inflammatory reactive states in astrocytes triggered by alpha-synuclein aggregation, and this may drive the neuroinflammatory cascade in Parkinson’s.
Adoptive transfer of mitochondrial antigen-specific CD8+T-cells in mice causes parkinsonism and compromises the dopamine system
Authors: Elemeery MN , Tchung A , Boulet S , Mukherjee S , Giguère N , Daudelin J-F , Even A , Hétu-Arbour R , Matheoud D , Stratton JA , Labrecque N , Trudeau L-E 
Published: February 2024

AbstractThe progressive dysfunction and degeneration of dopamine (DA) neurons of the ventral midbrain is linked to the development of motor symptoms in Parkinson’s disease (PD). Multiple lines of evidence suggest the implication of neuroinflammation and mitochondrial dysfunction as key drivers of neurodegenerative mechanisms in PD. Recent work has revealed that loss of the mitochondrial kinase PINK1 leads to enhanced mitochondrial antigen presentation (MitAP) by antigen-presenting cells (APCs), the amplification of mitochondrial antigen-specific CD8+T cells and the loss of DA neuron terminals markers in the brain in response to gut infection. However, whether mitochondrial antigen- specific T cells are involved in and/or sufficient to cause DA system dysfunction remains unclear. Here, we investigated the effect of mitochondrial autoimmunity by adoptively transferring mitochondrial peptide-specific CD8+T cells into wild-type (WT) and PINK1 KO mice. We find that this leads to L- DOPA-reversible motor impairment and to robust loss of DA neurons and axonal markers in the striatum in both PINK1 WT and KO mice. Our findings provide direct evidence of the pivotal role played by mitochondrial-specific CD8+T cell infiltration in the brain in driving PD-like pathology and the development of parkinsonism. Altogether, our data strongly support the hypothesis that MitAP and autoimmune mechanisms play a key role in the pathophysiological processes leading to PD.
Matching Excellence: ONT’s Rise to Parity with PacBio in Genome Reconstruction of Non-Model Bacterium with High GC Content
Authors: Soto-Serrano Axel , Li Wenwen , Panah Farhad M. , Hui Yan , Atienza Pablo , Fomenkov Alexey , Roberts Richard J. , Deptula Paulina , Krych Lukasz 
Published: February 2024

AbstractReconstruction of complete bacterial genomes is a vital aspect of microbial research, as it provides complex information about genetic content, gene ontology, and regulation. It has become a domain of 3rd generation, long-read sequencing platforms, as short-read technologies can deliver mainly fragmented genomes. PacBio platform can provide high-quality complete genomes, yet remains one of the most expensive sequencing strategies. Oxford Nanopore Technology (ONT) offers the advantage of producing the longest reads, being at the same time the most cost-effective option in terms of platform costs, as well as library preparation, and sequencing. However, ONTs error rate, although significantly reduced lately, still holds a certain level of distrust in the scientific community.In recent years, hybrid assembly of Nanopore and Illumina data has been used to solve ONTs issue with error rate and has yielded the best results in terms of genome completeness, quality, and price. However, the latest advancements in Nanopore technology, including new flow cells (R10.4.1), new library preparation chemistry (V14) and duplex-mode, updated basecallers (Dorado v0.4.1), and the realization that sequencing in dark mode results in significantly increased throughput, have had a significant impact on the quality of generated data and, thus, the recovery of complete genomes by ONT sequencing alone.In this study, we compared the data generated by ONT using three sequencing strategies (Native barcoding, RAPID barcoding, and custom-developed: BARSEQ) against PacBio and Illumina (NextSeq) as well as Illumina-ONT hybrid data. For this purpose, we employed three strains of the actinobacteriaPropionibacterium freudenreichii, whose genomes have been proven difficult to reconstruct due to high GC content, regions of repeated sequences and massive genome rearrangements.Our data indicate that DNA libraries prepared with the native barcoding kit, sequenced with V14 chemistry on R10.4.1 flow cell, and assembled with Flye resulted in the reconstruction of complete genomes of overall quality highly similar to that of genomes reconstructed with PacBio. The highest level of quality can be achieved by hybrid assembly of data from the Native barcoding kit complemented with data from custom-developed BARSEQ, both sequenced on R10.4.1 flow cell. In conclusion, our results demonstrate that ONT can be used as a cost-effective sequencing strategy, without the need for complementing with other sequencing technologies, for the reconstruction of complete genomes of the highest quality.
Neural Manifold Capacity Captures Representation Geometry, Correlations, and Task-Efficiency Across Species and Behaviors
Authors: Chou Chi-Ning , Arend Luke , Wakhloo Albert J. , Kim Royoung , Slatton Will , Chung SueYeon 
Published: February 2024

AbstractThe study of the brain encompasses multiple scales, including temporal, spatial, and functional aspects. To integrate understanding across these different levels and modalities, it requires developing quantification methods and frameworks. Here, we present effective Geometric measures from Correlated Manifold Capacity theory (GCMC) for probing the functional structure in neural representations. We utilize a statistical physics approach to establish analytical connections between neural co-variabilities and downstream read-out efficiency. These effective geometric measures capture both stimulus-driven and behavior-driven structures in neural population activities, while extracting computationally-relevant information from neural data into intuitive and interpretable analysis descriptors. We apply GCMC to a diverse collection of datasets with different recording methods, various model organisms, and multiple task modalities. Specifically, we demonstrate that GCMC enables a wide range of multi-scale data analysis. This includes quantifying the spatial progression of encoding efficiency across brain regions, revealing the temporal dynamics of task-relevant manifold geometry in information processing, and characterizing variances as well as invariances in neural representations throughout learning. Lastly, the effective manifold geometric measures may be viewed as order parameters for phases related to computational efficiency, facilitating data-driven hypothesis generation and latent embedding.
Emergence of bluetongue virus serotype 3 in western Germany, October 2023, andad-hocmonitoring inCulicoidesbiting midges
Authors: Voigt Anja , Kampen Helge , Heuser Elisa , Zeiske Sophie , Hoffmann Bernd , Höper Dirk , Holsteg Mark , Sick Franziska , Ziegler Sophia , Wernike Kerstin , Beer Martin , Werner Doreen 
Published: February 2024

AbstractBluetongue virus serotype 3 emerged in October 2023 in Germany, where Schmallenberg virus is enzootic. BTV-3 was detected in a pool ofCulicoidesbiting midges at the same time as infections were reported from ruminants. Schmallenberg virus was frequently found in vector pools, reflecting the epidemiological situation.One sentence summary lineCoinciding with the emergence and low-level circulation of bluetongue virus serotype 3 in ruminants in Germany in October 2023, the virus was detected in a pool ofCulicoidesbiting midges of the Obsoletus Group, while enzootic Schmallenberg virus was found in numerous midge pools.
Validation of a glycomics-based test associated with risk of HCC development in cirrhosis
Authors: Verhelst Xavier , Meuris Leander , Colman Roos , Geerts Anja , Van Hecke Annelies , Van Vlierberghe Hans , Callewaert Nico 
Published: February 2024

AbstractBackgroundCirrhosis is the main risk factor for the development of Hepatocellular carcinoma (HCC). Six-monthly screening with ultrasound is advocated for the surveillance of cirrhotic patients. We recently showed that a glycomics-based test (GlycoCirrhoTest [GCT]) can provide additional information regarding the risk of HCC development in cirrhotic patients.AimsIndependent clinical validation of the GCT for the assessment of the risk of HCC development in cirrhosis and exploration of additional clinical parameters to assess HCC risk.MethodsValidation study on serum samples of patients with established compensated cirrhosis (CHILD Pugh A & B) in a tertiary liver centre. Serum N-glycan profiling was performed and GCT was calculated at baseline. During the follow up period, patients were screened for the presence of HCC every 6 months with ultrasound.ResultsA total of 198 cirrhotic patients were followed in clinical routine for the development of HCC. 29 patients developed HCC and one died during follow up. At baseline, the mean GCT value was significantly higher in patients who developed HCC within 3 years compared to patients who did not develop HCC (Welch’s t-test, p-value 3 years: 0.034). A high GCT at baseline was associated with increased HCC incidence with a HR of 5.8 (95% CI: 0.7 – 48), 4.8 (95% CI: 1.4 – 16) and 3.6 (95% CI: 1.2 – 11) at 3, 5 and 7 years post sampling respectively. Results from this study are in agreement with previous results1, as shown in a meta-analysis. Moreover, we also identified albumin as an independent predictor for developing HCC in a multivariate analysis revealing that low albumin blood levels (< 4g/dL) are also associated with increased HCC incidence with a HR at 7 years of 2.3 (95% CI: 1.1 - 4.9). For subjects with both high GCT and low albumin we found a HR of 9.8 (95% CI: 3.5 to 27) at 7 years.ConclusionsGCT is a glycomics-based test that provides additional information for risk assessment of HCC development in cirrhosis. This information could be used to develop personalised HCC screening programs in cirrhotic patients according to the value of GCT. Serum albumin levels could provide additional and GCT-independent information which may add to the utility of the test.