bluuebunny/crossref_metadata_2025_split huggingface dataset:
Engineering Ca2+-dependent DNA polymerase activity
Authors: Biggs Bradley W. , de Paz Alexandra M. , Bhan Namita J. , Cybulski Thaddeus R. , Church George M. , Tyo Keith E. J. 
Published: May 2023

AbstractAdvancements in synthetic biology have provided new opportunities in biosensing with applications ranging from genetic programming to diagnostics. Next generation biosensors aim to expand the number of accessible environments for measurement, increase the number of measurable phenomena, and improve the quality of the measurement. To this end, an emerging area in the field has been the integration of DNA as an information storage medium within biosensor outputs, leveraging nucleic acids to record biosensor state over time. However, slow signal transduction steps, due to the timescales of transcription and translation, bottleneck many sensing-DNA recording approaches. DNA polymerases (DNAPs) have been proposed as a solution to the signal transduction problem by operating as both the sensor and responder, but there is presently a lack of DNAPs with functional sensitivity to many desirable target ligands. Here, we engineer components of the Pol δ replicative polymerase complex ofSaccharomyces cerevisiaeto sense and respond to Ca2+, a metal cofactor relevant to numerous biological phenomena. Through domain insertion and binding site grafting to Pol δ subunits, we demonstrate functional allosteric sensitivity to Ca2+. Together, this work provides an important foundation for future efforts in developing DNAP-based biosensors.
A common flanking variant is associated with enhanced meiotic stability of theFGF14-SCA27B locus
Authors: Pellerin David , Gobbo Giulia Del , Couse Madeline , Dolzhenko Egor , Dicaire Marie-Josée , Rebelo Adriana , Roth Virginie , Wandzel Marion , Bonnet Céline , Ashton Catherine , Lamont Phillipa J. , Laing Nigel G. , Renaud Mathilde , Ravenscroft Gianina , Houlden Henry , Synofzik Matthis , Eberle Michael A. , Boycott Kym M. , Pastinen Tomi ,   All of Us Long Reads Working Group, Brais Bernard , Zuchner Stephan , Danzi Matt C. 
Published: May 2023

AbstractThe factors driving initiation of pathological expansion of tandem repeats remain largely unknown. Here, we assessed theFGF14-SCA27B (GAA)•(TTC) repeat locus in 2,530 individuals by long-read and Sanger sequencing and identified a 5’-flanking 17-bp deletion-insertion in 70.34% of alleles (3,463/4,923). This common sequence variation was present nearly exclusively on alleles with fewer than 30 GAA-pure repeats and was associated with enhanced meiotic stability of the repeat locus.
Cost-effectiveness of a telemonitoring program in patients with cardiovascular diseases compared to standard of care
Authors: Ziegler Andreas , Öner Alper , Quadflieg Gisela , Betschart Raphael O , Thiéry Alexandre , Babel Hugo , Mwambi Henry G , Neumeyer Henriette , Mackschin Steffen , Hintz Sissy , Mann Miriam , Dittrich Hermann , Schmidt Christian 
Published: May 2023

AbstractObjectivesThe main aim of this work was to analyze the cost-effectiveness of an integrated care concept (NICC) that combines telemonitoring with the support of a care center in addition to guideline therapy for patients. Secondary aims were to compare health utility and health-related quality of life (QoL) between NICC and standard of care (SoC).MethodsThe randomized controlled CardioCare MV trial compared NICC and SoC in patients from Mecklenburg-West Pomerania (Germany) with atrial fibrillation, heart failure, or treatment-resistant hypertension. QoL was measured using the EQ-5D-5L at baseline, 6 months, and 1 year follow-up. Quality-adjusted life-years (QALY), EQ5D utility scores, visual analogue scale (VAS) scores, and VAS adjusted life-years (VAS-AL) were calculated. Cost data were obtained from health insurance companies, and the payer perspective was taken in health economic analyses. Quantile regression was used with adjustments for stratification variables.ResultsThe net benefit of NICC (QALY) was 0.031 (95%CI: 0.012–0.050; p=0.001) in this trial involving 957 patients. EQ5D index values, VAS-ALs and VAS were larger for NICC compared to SoC at 1 year follow-up (all p≤0.004). Direct cost per patient and year were €323 (CI: €157–489) lower in the NICC group. When 2000 patients are served by the care center, NICC is cost-effective if one is willing to pay 10,652€ per QALY per year.ConclusionNICC was associated with higher QoL and health utility. The program is cost-effective if one is willing to pay approximately 11,000€ per QALY per year.WHAT IS ALREADY KNOWN ON THIS TOPICIntegrated care concepts, i.e., the combination of telemedicine and the reinforcement of patient self-care in a multidisciplinary team together with telephone support, reduce mortality, morbidity, and levels of depression in patients with cardiovascular diseases.WHAT THIS STUDY ADDSThe integrated care concept investigated in the CardioCare MV trial was also associated with higher quality of life, higher health utility, and it is cost-effective if one is willing to pay approximately 11,000 € per quality-adjusted life-year (QALY).HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYWith the demonstrated cost effectiveness of the integrated care concept, policy makers and health insurance companies are enabled to decide on the introduction of these concepts as standard of care.
Integrative single-nucleus multi-omics analysis prioritizes candidatecisandtransregulatory networks and their target genes in Alzheimer’s disease brains
Authors: Gamache Julia , Gingerich Daniel , Shwab E. Keats , Barrera Julio , Garrett Melanie E. , Hume Cordelia , Crawford Gregory E. , Ashley-Koch Allison E. , Chiba-Falek Ornit 
Published: May 2023

ABSTRACTBackgroundThe genetic underpinnings of late-onset Alzheimer’s disease (LOAD) are yet to be fully elucidated. Although numerous LOAD-associated loci have been discovered, the causal variants and their target genes remain largely unknown. Since the brain is composed of heterogenous cell subtypes, it is imperative to study the brain on a cell subtype specific level to explore the biological processes underlying LOAD.MethodsHere, we present the largestparallelsingle-nucleus (sn) multi-omics study to simultaneously profile gene expression (snRNA-seq) and chromatin accessibility (snATAC-seq) to date, using nuclei from 12 normal and 12 LOAD brains. We identified cell subtype clusters based on gene expression and chromatin accessibility profiles and characterized cell subtype-specific LOAD-associated differentially expressed genes (DEGs), differentially accessible peaks (DAPs) andcisco-accessibility networks (CCANs).ResultsIntegrative analysis defined disease-relevant CCANs in multiple cell subtypes and discovered LOAD-associated cell subtype specific candidatecisregulatory elements (cCREs), their candidate target genes, andtrans-interacting transcription factors (TFs), some of which were LOAD-DEG, for example,ELK1in excitatory neurons (Exc1) andKLF13andJUN, found in multiple cell subtypes. Finally, we focused on a subset of cell subtype-specific CCANs that overlap known LOAD-GWAS regions and catalogued putative functional SNPs changing the affinities of TF motifs within LOAD-cCREs linked to LOAD-DEGs including,APOEandMYO1Ein a specific subtype of microglia andBIN1in a subpopulation of oligodendrocytes.ConclusionsTo our knowledge, this study represents the most comprehensive systematic interrogation to date of regulatory networks and the impact of genetic variants on gene dysregulation in LOAD at a cell subtype resolution. Our findings revealed crosstalk between epigenetic, genomic, and transcriptomic determinates of LOAD pathogenesis and define catalogues of candidate genes, cCREs, and variants involved in LOAD genetic etiology and the cell subtypes in which they act to exert their pathogenic effects. Overall, these results suggest that cell subtype-specificcis-transinteractions between regulatory elements and TFs, and the genes dysregulated by these networks contribute to the development of LOAD.
Highly pathogenic avian influenza causes mass mortality in Sandwich tern (Thalasseus sandvicensis) breeding colonies across northwestern Europe
Authors: Knief Ulrich , Bregnballe Thomas , Alfarwi Ibrahim , Ballmann Mónika , Brenninkmeijer Allix , Bzoma Szymon , Chabrolle Antoine , Dimmlich Jannis , Engel Elias , Fijn Ruben , Fischer Kim , Hälterlein Bernd , Haupt Matthias , Hennig Veit , Herrmann Christof , in ‘t Veld Ronald , Kirchhoff Elisabeth , Kristersson Mikael , Kühn Susanne , Larsson Kjell , Larsson Rolf , Lawton Neil , Leopold Mardik , Lilipaly Sander , Lock Leigh , Marty Régis , Matheve Hans , Meissner Włodzimierz , Morisson Paul , Newton Stephen , Olofsson Patrik , Packmor Florian , Pedersen Kjeld T. , Redfern Chris , Scarton Francesco , Schenk Fred , Scher Olivier , Serra Lorenzo , Smith Julian , Smith Wez , Sterup Jacob , Stienen Eric , Strassner Viola , Valle Roberto G. , van Bemmelen Rob S. A. , Veen Jan , Vervaeke Muriel , Weston Ewan , Wojcieszek Monika , Courtens Wouter 
Published: May 2023

AbstractIn 2022, highly pathogenic avian influenza (HPAI) A(H5N1) virus clade 2.3.4.4b became enzootic and caused mass mortality in Sandwich terns and other seabird species across northwestern Europe. We present data on characteristics of the spread of the virus between breeding colonies and the number of dead adult Sandwich terns recorded at breeding sites throughout northwestern Europe. Within two months after the first mortalities were reported, in total 20,531 adult Sandwich terns were found dead, which is >17% of the total northwestern European breeding population. Losses are likely higher, as we expect that many victims were not found (mortality rate might be up to 74% of the breeding population). Inside the colonies almost all chicks died. After the peak of the outbreak, in a colony established by late breeders, 25.7% of adults showed immunity against HPAI subtype H5. Removal of carcasses helped in reducing the spread of the disease and consequently total mortality. More research on the sources and modes of transmission, incubation times, effective containment and immunity is urgently needed to combat this major threat for colonial seabirds.
Population genomics of harbour sealPhoca vitulinafrom northern British Columbia through California and comparison to the Atlantic subspecies
Authors: Sutherland Ben J. G. , Rycroft Claire , Duguid Ashtin , Beacham Terry D. , Tucker Strahan 
Published: May 2023

AbstractThe harbour sealPhoca vitulinais a ubiquitous pinniped species found throughout coastal waters of the Northern Hemisphere. Harbour seal impacts on ecosystem dynamics may be significant due to their high abundance and food web position. Two subspecies exist in North America,P. v. richardiiin the Pacific Ocean, andP. v. vitulinain the Atlantic. Strong natal philopatry of harbour seals can result in fine-scale genetic structure and isolation-by-distance. Management of harbour seals is expected to benefit from improved resolution of seal population structure and dynamics. Here we use genotyping-by-sequencing to genotype 146 harbour seals from the eastern Pacific Ocean (i.e., British Columbia (BC), Oregon, and California) and the western Atlantic Ocean (i.e., Québec, Newfoundland, and Labrador). Using 12,742 identified variants, we confirm the recently identified elevated genetic diversity in the eastern Pacific relative to the western Atlantic and greatest differentiation between the subspecies. Further, we demonstrate that this is independent of reference genome bias or other potential technical artefacts. Coast-specific analyses with 8,933 and 3,828 variants in Pacific and Atlantic subspecies, respectively, identify divergence between BC and Oregon-California, and between Québec and Newfoundland-Labrador. Unexpected PCA outlier clusters were observed in two populations due to cryptic relatedness of individuals; subsequently, closely related samples were removed. Admixture analysis indicates an isolation-by-distance signature where Oregon seals contained some of the BC signature, whereas California did not. Additional sampling is needed in the central and north coast of BC to determine whether a discrete separation of populations exists within the region.
MsQuality – an interoperable open-source package for the calculation of standardized quality metrics of mass spectrometry data
Authors: Naake Thomas , Rainer Johannes , Huber Wolfgang 
Published: May 2023

AbstractMotivationMultiple factors can impact accuracy and reproducibility of mass spectrometry data. There is a need to integrate quality assessment and control into data analytic workflows.ResultsTheMsQualitypackage calculates 40 low-level quality metrics based on the controlled mzQC vocabulary defined by the HUPO-PSI on a single mass spectrometry-based measurement of a sample. It helps to identify low-quality measurements and track data quality. Its use of community-standard quality metrics facilitates comparability of quality assessment and control (QA/QC) criteria across datasets.AvailabilityThe R packageMsQualityis available through Bioconductor athttps://bioconductor.org/packages/MsQuality.Contactnaake@embl.deSupplementary informationSupplementary data are available online.
How Older Adults Regulate Lateral Stepping on Narrowing Walking Paths
Authors: Kazanski Meghan E. , Cusumano Joseph P. , Dingwell Jonathan B. 
Published: May 2023

ABSTRACTWalking humans often navigate complex, varying walking paths. To reduce falls, we must first determine how older adults purposefully vary their steps in contexts that challenge balance. Here, 20 young (21.7±2.6 yrs) and 18 older (71.6±6.0 yrs) healthy adults walked on virtual paths that slowly narrowed (from 45 cm to as narrow as 5 cm). Participants could switch onto an “easier” path whenever they chose. We applied our Goal Equivalent Manifold framework to quantify how participants adjusted their lateral stepping variability and step-to-step corrections of step width and lateral position as these paths narrowed. We also extracted these characteristics where participants switched paths. As paths narrowed, all participants reduced their lateral stepping variability, but older adults less so. To stay on the narrowing paths, young adults increasingly corrected step-to-step deviations in lateral position more, by correcting step-to-step deviations in step widthless. Conversely, as older adults also increasingly corrected lateral position deviations, they did sowithoutsacrificing correcting step-to-step deviations in step width, presumably to preserve balance. While older adults left the narrowing paths sooner, several of their lateral stepping characteristics remained similar to those of younger adults. While older adults largely maintained overall walking performanceper se, they did so by changing how they balanced the competing stepping regulation requirements intrinsic to the task: maintaining position vs. step width. Thus, balancing how to achieve multiple concurrent stepping goals while walking provides older adults the flexibility they need to appropriately adapt their stepping on continuously narrowing walking paths.
Demographic effects of aggregation in the presence of a component Allee effect
Authors: Jorge Daniel C.P. , Martinez-Garcia Ricardo 
Published: May 2023

AbstractIntraspecific interactions are key drivers of population dynamics because they establish relations between individual fitness and population density. The component Allee effect is defined as a positive correlation between any fitness component of a focal organism and population density, and it can lead to positive density dependence in the population per capita growth rate. The spatial population structure is key to determining whether and to which extent a component Allee effect will manifest at the demographic level because it determines how individuals interact with one another. However, existing spatial models to study the Allee effect impose a fixed spatial structure, which limits our understanding of how a component Allee effect and the spatial dynamics jointly determine the existence of demographic Allee effects. To fill this gap, we introduce a spatially-explicit theoretical framework where spatial structure and population dynamics are emergent properties of the individual-level demographic and movement rates. Depending on the intensity of the individual-level processes the population exhibits a variety of spatial patterns, including evenly spaced aggregates of organisms, that determine the demographic-level by-products of an existing individual-level component Allee effect. We find that aggregation increases population abundance and allows populations to survive in harsher environments and at lower global population densities when compared with uniformly distributed organisms. Moreover, aggregation can prevent the component Allee effect from manifesting at the population level or restrict it to the level of each independent group. These results provide a mechanistic understanding of how component Allee effects might operate for different spatial population structures and show at the population level. Because populations subjected to demographic Allee effects exhibit highly nonlinear dynamics, especially at low abundances, our results contribute to better understanding population dynamics in the presence of Allee effects and can potentially inform population management strategies.
The clathrin adaptor AP-1B independently controls proliferation and differentiation in the mammalian intestine
Authors: Duclos Maela , Bourdais Anne , Nicolle Ophélie , Michaux Grégoire , Bidaud-Meynard Aurélien 
Published: May 2023

AbstractMaintenance of the polarity of the epithelial cells facing the lumen of the small intestine is crucial to ensure the vectorial absorption of nutrients as well as the integrity of the apical brush border and the intestinal barrier. Polarized vesicular trafficking plays a key role in this process, and defective transport due to mutations in apical trafficking-related genes has been shown to affect nutrient absorption. Interestingly, it has been demonstrated that downregulation of the polarized sorting clathrin adaptor AP-1B led to both epithelial polarity and proliferation defects in the mouse intestine. This enlightened a new function of polarized trafficking in the gut epithelium and a novel link between trafficking, polarity, and proliferation. Here, using CRISPR-Cas9-mediated mutation of the AP-1B coding geneAp1m2in mouse intestinal organoids, we uncovered a novel proliferation pathway controlled by AP-1B. We showed that the polarity defects induced byAp1m2mutations led to a defective apical targeting of both Rab11+apical recycling endosomes and of the polarity determinant Cdc42. Moreover, we showed that these polarity defects were accompanied by an induction of YAP and EGFR/mTOR-dependent proliferation pathways. Finally, we showed that AP-1B additionally controlled a proliferation-independent differentiation pathway towards the secretory lineage. Overall, our results highlighted the pleiotropic roles played by AP-1B in the homeostasis of the gut epithelium.
Towards substitution of invasive telemetry: An integrated home cage concept for unobstrusive monitoring of objective physiological parameters in rodents
Authors: Mösch Lucas , Kunczik Janosch , Breuer Lukas , Merhof Dorit , Gass Peter , Potschka Heidrun , Zechner Dietmar , Vollmar Brigitte , Tolba René , Häager Christine , Bleich André , Czaplik Michael , Pereira Carina Barbosa 
Published: May 2023

AbstractThis study presents a novel concept for a smart cage designed to monitor the physiological parameters of mice and rats in animal-based experiments. The system focuses on monitoring key clinical parameters, including heart rate, respiratory rate, body temperature, activity, and circadian rhythm. To create the smart home cage system, an in-depth analysis of the requirements was performed, including camera positioning, imaging system types, resolution, frame rates, external illumination, video acquisition, data storage, and synchronization. Two different camera perspectives were considered, and specific camera models, including two near-infrared and two thermal cameras, were selected to meet the requirements. During the first testing phase, the system demonstrated the potential of extracting vital parameters such as respiratory and heart rate. This technology has the potential to reduce the need for implantable sensors while providing reliable and accurate physiological data, leading to refinement and improvement in laboratory animal care.
Development of compact transcriptional effectors using high-throughput measurements in diverse contexts
Authors: Tycko Josh , Van Mike V. , Aradhana  , DelRosso Nicole , Yao David , Xu Xiaoshu , Ludwig Connor , Spees Kaitlyn , Liu Katherine , Hess Gaelen T , Gu Mingxin , Mukund Adi Xiyal , Suzuki Peter H. , Kamber Roarke A. , Qi Lei S. , Bintu Lacramioara , Bassik Michael C. 
Published: May 2023

AbstractHuman nuclear proteins contain >1000 transcriptional effector domains that can activate or repress transcription of target genes. We lack a systematic understanding of which effector domains regulate transcription robustly across genomic, cell-type, and DNA-binding domain (DBD) contexts. Here, we developed dCas9-mediated high-throughput recruitment (HT-recruit), a pooled screening method for quantifying effector function at endogenous targets, and tested effector function for a library containing 5092 nuclear protein Pfam domains across varied contexts. We find many effectors depend on target and DBD contexts, such as HLH domains that can act as either activators or repressors. We then confirm these findings and further map context dependencies of effectors drawn from unannotated protein regions using a larger library containing 114,288 sequences tiling chromatin regulators and transcription factors. To enable efficient perturbations, we select effectors that are potent in diverse contexts, and engineer (1) improved ZNF705 KRAB CRISPRi tools to silence promoters and enhancers, and (2) a compact human activator combination NFZ for better CRISPRa and inducible circuit delivery. Together, this effector-by-context functional map reveals context-dependence across human effectors and guides effector selection for robustly manipulating transcription.
Cryo-electron tomography reveals postsynaptic nanoblocks in excitatory synapses
Authors: Sun Rong , Allen James P , Wilson Liana , Haider Mariam , Alten Baris , Zhou Zimeng , Wang Xinyi , Zhou Qiangjun 
Published: May 2023

AbstractThe nanoscale organization of proteins within synapses is critical for maintaining and regulating synaptic transmission and plasticity. Here, we use cryogenic electron tomography to directly visualize the three-dimensional architecture and supramolecular organization of pre-cleft-postsynaptic components in their near-native cellular context in both synaptosomes from rat hippocampi and synapses from rat primary cultured neurons. High-resolution electron microscopy and quantitative analyses revealed that postsynaptic density (PSD) is composed of membrane-associated nanoblocks of various sizes, which are in close relationship with potential presynaptic release sites through adhesion molecules spanning the synaptic cleft, as well as with post-synaptic receptors. Subtomogram averaging from synaptosomes showed two distinct types of postsynaptic membrane proteins at resolutions of 24 Å and 26 Å respectively. Furthermore, our data reveal that majority of potential release sites and ∼50% subtomogram averaged receptor-like particles are located within the boundary of PSD nanoblocks, while PSD nanoblocks might be redundant for neurotransmission. The results of this study provide a more comprehensive understanding of synaptic ultrastructure and suggest that PSD is composed of clustering of various nanoblocks, which likely underlies the dynamic nature of PSD to modulate synaptic strength.