bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multimodal Object Representations Rely on Integrative Coding
Authors: Li Aedan Y. , Ladyka-Wojcik Natalia , Qazilbash Heba , Golestani Ali , Walther Dirk B. , Martin Chris B. , Barense Morgan D. 
Published: September 2022

AbstractCombining information from multiple senses is essential to object recognition. Yet how the mind combines sensory input into coherent multimodal representations – the multimodal binding problem – remains poorly understood. Here, we applied multi-echo fMRI across a four-day paradigm, in which participants learned 3-dimensional multimodal object representations created from well-characterized visual shape and sound features. Our novel paradigm decoupled the learned multimodal object representations from their baseline unimodal shape and sound features, thus tracking the emergence of multimodal concepts as they were learned by healthy adults. Critically, the representation for the whole object was different from the combined representation of its individual parts, with evidence of an integrative object code in anterior temporal lobe structures. Intriguingly, the perirhinal cortex – an anterior temporal lobe structure – was by default biased towards visual shape, but this initial shape bias was attenuated with learning. Pattern similarity analyses suggest that after learning the perirhinal cortex orthogonalized combinations of visual shape and sound features, transforming overlapping feature input into distinct multimodal object representations. These results provide evidence of integrative coding in the anterior temporal lobes that is distinct from the distributed sensory features, advancing the age-old question of how the mind constructs multimodal objects from their component features.
An RNA sequence that reprograms ribosomes to bypass a 50 nucleotide coding gap is encoded by a mobile element whose sequence conservation illuminates its bypass mechanisms
Authors: Manning Gerard , Atkins John F 
Published: September 2022

AbstractBackgroundA remarkable sequence in phage T4 causes ribosomes to skip over a 50 nucleotide insert within a topoisomerase subunit gene, and resume correct synthesis of the protein at a high efficiency. Its mechanism has been extensively studied but it remained an isolated phenomenon whose origin and full function are still a mystery.ResultsWe have found dozens of homologous cases in genomic and metagenomic sequences, all part of a mobile DNA element that repeatedly inserts in topoisomerase genes of Myoviridae phages. These have substantial sequence diversity, with selective conservation that specify the elaborate set of mechanisms found experimentally to underlie this extreme case of translational recoding. These sequences provide new variations on these mechanisms, and introduce additional features that may also be important for bypassing. These include a series of RNA secondary structures, a conserved stop codon or rare ‘hungry’ codon at the start of the bypass, a Shine-Dalgarno sequence flanked by AU-rich sequence, and residues in the nascent peptide that prime the ribosome for bypassing.ConclusionsThese data provide an evolutionary foundation for the experimentally derived mechanisms, highlight several new features of the sequence, and provide substantial new variations on the bypass theme that will allow further experimental exploration of biologically meaningful variants.
Glioblastoma disrupts cortical network activity at multiple spatial and temporal scales
Authors: Meyer Jochen , Yu Kwanha , Luna-Figueroa Estefania , Deneen Ben , Noebels Jeffrey 
Published: September 2022

AbstractThe emergence of glioblastoma in cortical tissue initiates early and persistent neural hyperexcitability with signs ranging from mild cognitive impairment to convulsive seizures. The influence of peritumoral synaptic density, growth dynamics, and spatial contours of excess glutamate upon higher order neuronal network modularity is unknown. We combined cellular and widefield imaging of calcium and glutamate fluorescent reporters in two GBM mouse models with distinct synaptic microenvironments and growth profiles. Functional metrics of neural ensembles are dysregulated during tumor invasion depending on the stage of malignant progression and tumor cell proximity. Neural activity is significantly elevated during periods of accelerated tumor growth. Abnormal glutamate accumulation precedes and outpaces the spatial extent of baseline neuronal calcium signaling, indicating these processes are uncoupled in tumor cortex. Distinctive excitability homeostasis patterns and functional connectivity of local and remote neuronal populations support the promise of precision genetic diagnosis and management of this devastating brain disease.
Complex aneuploidy triggers autophagy and p53-mediated apoptosis and impairs the second lineage segregation in human preimplantation embryos
Authors: Regin Marius , Lei Yingnan , De Deckersberg Edouard Couvreu , Janssens Charlotte , Huyghebaert Anfien , Guns Yves , Verdyck Pieter , Verheyen Greta , Van de Velde Hilde , Sermon Karen , Spits Claudia 
Published: September 2022

AbstractAbout 70% of human cleavage stage embryos show chromosomal mosaicism, falling to 20% in blastocysts. Chromosomally mosaic human blastocysts can implant and lead to healthy new-borns with normal karyotypes. Studies in mouse embryos and human gastruloids have shown that aneuploid cells show proteotoxic stress, autophagy and p53 activation and that they are eliminated from the epiblast by apoptosis while being tolerated in the trophectoderm. These observations suggest a selective loss of aneuploid cells from human embryos, but the underlying mechanisms are not yet fully understood. In this study we investigated the cellular consequences of aneuploidy in a total of 125 human blastocysts. RNA-sequencing of trophectoderm cells showed transcriptional signatures of activated p53 pathway and apoptosis, which was proportionate to the level of chromosomal imbalance. Immunostaining corroborated that aneuploidy triggers proteotoxic stress, autophagy, p53-signalling, and apoptosis independent from DNA damage. Total cell numbers were lower in aneuploid embryos, due to a decline both in trophectoderm and in epiblast/primitive endoderm cell numbers. While lower cell numbers in trophectoderm may be attributed to apoptosis, it appeared that aneuploidy impaired the second lineage segregation, particularly primitive endoderm formation. This might be reinforced by retention of NANOG in aneuploid embryos. Our findings might explain why fully aneuploid embryos fail to further develop and we hypothesize that the same mechanisms lead to removal of aneuploid cells from mosaic embryos. This hypothesis needs further study as we did not analyze chromosomal mosaic embryos. Finally, we demonstrated a few differences with previous findings in the mouse, emphasizing the need for human embryo research to understand the consequences of aneuploidy.
Transcriptome profiling of tendon fibroblasts at the onset of embryonic muscle contraction reveals novel force-responsive genes
Authors: Nayak Pavan K , Subramanian Arul , Schilling Thomas F 
Published: September 2022

AbstractMechanical forces play a critical role in tendon development and function, influencing cell behavior through mechanotransduction signaling pathways and subsequent extracellular matrix (ECM) remodeling. Here we investigate the molecular mechanisms by which tenocytes in developing zebrafish embryos respond to muscle contraction forces during the onset of swimming and cranial muscle activity. Using genome-wide bulk RNA sequencing of FAC-sorted tenocytes we identify novel tenocyte markers and genes involved in tendon mechanotransduction. Embryonic tendons show dramatic changes in expression of Matrix Remodeling Associated 5b (mxra5b), Matrilin 1 (matn1), and the transcription factor Kruppel-like factor 2a (klf2a), as muscles start to contract. Using embryos paralyzed either by loss of muscle contractility or neuromuscular stimulation we confirm that muscle contractile forces influence the spatial and temporal expression patterns of all three genes. Quantification of these gene expression changes across tenocytes at multiple tendon entheses and myotendinous junctions reveals that their responses depend on force intensity, duration and tissue stiffness. These force-dependent feedback mechanisms in tendons, particularly in the ECM, have important implications for improved treatments of tendon injuries and atrophy.
Growth hormone receptor (GHR) in AgRP neurons regulates thermogenesis in aged mice in a sex-specific manner
Authors: Stilgenbauer Lukas , de Lima Juliana Bezerra Medeiros , Debarba Lucas Kniess , Khan Manal , Koshko Lisa , Kopchick John J. , Bartke Andrzej , Schneider Augusto , Sadagurski Marianna 
Published: September 2022

AbstractEvidence for hypothalamic regulation of energy homeostasis and thermoregulation in brown adipose tissue (BAT) during aging has been well recognized, yet the central molecular mediators involved in this process are poorly understood. The arcuate hypothalamus (ARC), orexigenic agouti-related peptide (AgRP) neurons control nutrient intake, energy homeostasis, and BAT thermogenesis. To determine the roles of growth hormone receptor (GHR) signaling in the AgRP neurons we used mice with the AgRP-specific GHR deletion (AgRPΔGHR). We found that female AgRPΔGHRmice were resistant to temperature adaptation, and their body core temperature remained significantly lower when held at 10°C, 22°C, or 30°C, compared to control mice. Low body core temperature in female AgRPΔGHRmice has been associated with significant reductions inUcp1andPgc1αexpression in the BAT. Further, neuronal activity in AgRP in response to cold exposure was blunted in AgRPΔGHRfemales, while the number of Fos+AgRP neurons was increased in control females exposed to cold. Global transcriptome from BAT identified increased expression of genes related to immune responses and chemokine activity and decreased expression of genes involved in triglycerides synthesis and metabolic pathways in AgRPΔGHRfemales. Importantly, these were the same genes that are downregulated by thermoneutrality in control mice but not in the AgRPΔGHRanimals. Collectively, these data demonstrate a novel circuit of thermal regulation between the hypothalamic AgRP-GHR and BAT and provide insight into the brain systems that are critical for the thermogenic vitality of the elderly.
An automatic entropy method to efficiently mask histology whole-slide images
Authors: Song Yipei , Cisternino Francesco , Mekke Joost M. , de Borst Gert J. , de Kleijn Dominique P.V. , Pasterkamp Gerard , Vink Aryan , Glastonbury Craig A. , van der Laan Sander W. , Miller Clint L. 
Published: September 2022

AbstractBackgroundTissue segmentation of histology whole-slide images (WSI) remains a critical task in automated digital pathology workflows for both accurate disease diagnosis and deep phenotyping for research purposes. This is especially challenging when the tissue structure of biospecimens is relatively porous and heterogeneous, such as for atherosclerotic plaques.MethodsIn this study, we developed a unique approach called EntropyMasker based on image entropy to tackle the fore- and background segmentation (masking) task in histology WSI. We evaluated our method on 97 high-resolution WSI of human carotid atherosclerotic plaques in the Athero-Express Biobank Study, constituting hematoxylin and eosin (H&E) and 8 other staining types.Results and ConclusionUsing multiple benchmarking metrics, we compared our method with four widely used segmentation methods: Otsu’s method, Adaptive mean, Adaptive Gaussian and slideMask and observed that our method had the highest sensitivity and Jaccard similarity index. We envision EntropyMasker to fill an important gap in WSI preprocessing and deep learning image analysis pipelines and enable disease phenotyping beyond the field of atherosclerosis.
Criteria to Achieve Safe Antimicrobial Intravenous-to-Oral Switch in Hospitalised Adult Populations: A Systematic Rapid Review
Authors: Harvey Eleanor J , McLeod Monsey , De Brún Caroline , Ashiru-Oredope Diane 
Published: September 2022

AbstractIntroductionAntimicrobial stewardship and patient safety strategies include early intravenous-to-oral switch (IVOS) for antimicrobials.AimThis rapid review aimed to assess and collate IVOS criteria from the literature to achieve safe and effective antimicrobial IVOS in the hospital inpatient adult population.MethodThe rapid review follows the PRISMA statement and is registered with PROSPERO. Systematic literature searches were conducted. Articles of adult populations published between 2017-2021 were included. IVOS criteria from UK hospital IVOS policies were categorised to inform the framework synthesis of the literature criteria.ResultsIVOS criteria from 45/164 (27%) UK IVOS policies were categorised into a 5-section framework: 1-Timing of IV antimicrobial review, 2-Clinical signs and symptoms, 3-Infection markers, 4-Enteral route, and 5-Infection exclusions. The literature search identified 477 papers, of which 16 were included. The most common timing for review was 48-72 hours from initiation of intravenous antimicrobial (n=5, 30%). Nine studies (56%) stated clinical signs and symptoms must be improving. Temperature was the most frequently mentioned infection marker (n=14, 88%). Endocarditis had the highest mention as an infection exclusion (n=12, 75%). Overall, 33 IVOS criteria were identified to go forward into the Delphi process.ConclusionThrough the rapid review, 33 IVOS criteria were collated and presented within 5 distinct and comprehensive sections. The literature highlighted the possibility of reviewing IVOS before 48-72 hours, and of presenting HR, BP and RR as a combination early warning score criterion. The criteria identified can serve as a starting point of IVOS criteria review for any institution globally, as no country or region limits were applied. Further research is required to achieve consensus on IVOS criteria from healthcare professionals that manage patients with infections.What is already known on this topicAntimicrobial intravenous-to-oral switch has benefits such as decreased risk of catheter-related infections, reduced equipment costs and increased patient mobility and comfort. Acute hospitals often develop and implement individualised IVOS policies with varying levels of evidence base.What this study addsThis study provides evidence-based IVOS criteria to standardise practice in hospital settings.How this study might affect research, practice or policyIVOS criteria can be taken forward through a consensus process with healthcare professionals providing the care for hospitalised adult patients and making the decisions regarding infection management. In the acute hospital setting, IVOS criteria can be operationalised to promote best practice. The criteria can also be considered as part of organisation-wide audits and quality/policy incentives.
Childhood obesity is linked to putative neuroinflammation in brain white matter, hypothalamus, and striatum
Authors: Li Zhaolong , Samara Amjad , Ray Mary Katherine , Rutlin Jerrel , Raji Cyrus A. , Shimony Joshua S. , Sun Peng , Song Sheng-Kwei , Hershey Tamara , Eisenstein Sarah A. 
Published: September 2022

AbstractNeuroinflammation is both a consequence and driver of overfeeding and weight gain in rodent obesity models. Advances in magnetic resonance imaging (MRI) enable investigations of brain microstructure that suggests neuroinflammation in human obesity. To assess the convergent validity across MRI techniques and extend previous findings, we used diffusion basis spectrum imaging (DBSI) to characterize obesity-associated alterations in brain microstructure in 601 children (age 9-11 years) from the Adolescent Brain Cognitive DevelopmentSMStudy. Compared to children with normal-weight, greater DBSI restricted fraction (RF), reflecting neuroinflammation-related cellularity, was seen in widespread white matter in children with overweight and obesity. Greater DBSI-RF in hypothalamus, caudate nucleus, putamen, and, in particular, nucleus accumbens, correlated with higher baseline body mass index (BMI) and related anthropometrics. Comparable findings were seen in the striatum with a previously reported restriction spectrum imaging (RSI) model. Gain in waist circumference over one and two years related, at nominal significance, to greater baseline RSI-assessed restricted diffusion in nucleus accumbens and caudate nucleus, and DBSI-RF in hypothalamus, respectively. Here we demonstrate that childhood obesity is associated with microstructural alterations in white matter, hypothalamus, and striatum. Our results also support the reproducibility, across MRI methods, of findings of obesity-related putative neuroinflammation in children.
A MAD7-based genome editing system for E. coli
Authors: Mund Markus , Weber Wadim , Degreif Daniel , Schiklenk Christoph 
Published: September 2022

AbstractA broad variety of biomolecules is industrially produced in bacteria and yeasts. These microbial expression hosts can be optimized through genomic engineering using CRISPR tools. Here, we designed and characterized such a modular genome editing system based on the Cas12a-like RNA guided nuclease MAD7 in E. coli. Our system enables the efficient generation of single nucleotide polymorphisms (SNPs) or gene deletions and can directly be used with donor DNA from benchtop DNA assembly to increase throughput. We combined multiple edits to engineer an E. coli strain with reduced overflow metabolism and increased plasmid yield, highlighting the versatility and industrial applicability of our approach.
Nuclear-enriched protein phosphatase 4 ensures outer kinetochore assembly prior to nuclear dissolution
Authors: Rocha Helder , Simões Patrícia A. , Budrewicz Jacqueline , Lara-Gonzalez Pablo , Carvalho Ana Xavier , Dumont Julien , Desai Arshad , Gassmann Reto 
Published: September 2022

ABSTRACTA landmark event in the transition from interphase to mitosis in metazoans is nuclear envelope breakdown (NEBD). Many events important for mitosis occur prior to NEBD, including condensation of replicated chromosomes and assembly of kinetochores to rapidly engage spindle microtubules. Here we show that nuclear-enriched protein phosphatase 4 (PP4) ensures robust assembly of the microtubule-coupling outer kinetochore prior to NEBD. In the absence of PP4, chromosomes exhibit extended monopolar orientation after NEBD and subsequently mis-segregate. A secondary consequence of diminished outer kinetochore assembly is defective sister chromatid resolution. After NEBD, a cytoplasmic activity compensates for PP4 loss, leading to outer kinetochore assembly and recovery of chromosomes from monopolar orientation to significant biorientation. The Ndc80-Ska microtubule-binding module of the outer kinetochore is required for this recovery. PP4 associates with the inner kinetochore protein CENP-C; however, disrupting the PP4–CENP-C interaction does not perturb chromosome segregation. These results establish that PP4-dependent outer kinetochore assembly prior to NEBD is critical for timely and proper engagement of chromosomes with spindle microtubules.
High-grade serous ovarian carcinoma organoids as models of chromosomal instability
Authors: Vias Maria , Morrill Gavarró Lena , Sauer Carolin M. , Sanders Debbie , Piskorz Anna M. , Couturier Dominique-Laurent , Ballereau Stéphane , Hernando Barbara , Hall James , Correia-Martins Filipe , Markowetz Florian , Macintyre Geoff , Brenton James D. 
Published: September 2022

AbstractHigh-grade serous ovarian carcinoma (HGSOC) is the most genomically complex cancer, characterised by ubiquitous TP53 mutation, profound chromosomal instability and heterogeneity. The mutational processes driving chromosomal instability in HGSOC can be distinguished by specific copy number signatures. To develop clinically relevant models of these mutational processes we derived 15 continuous HGSOC patient-derived organoids (PDOs). We carried out detailed bulk transcriptomic, bulk genomic, single cell genomic, and drug sensitivity characterisation of the organoids. We show that PDOs comprise communities of different clonal populations and represent models of different causes of chromosomal instability including homologous recombination deficiency, chromothripsis, tandem-duplicator phenotype and whole genome duplication. We also show that these PDOs can be used as exploratory tools to study transcriptional effects of copy number alterations as well as compound-sensitivity tests. In summary, HGSOC PDO cultures provide a genomic tool for studies of specific mutational processes and precision therapeutics.
Physics-based generative model of curvature sensing peptides; distinguishing sensors from binders
Authors: van Hilten Niek , Methorst Jeroen , Verwei Nino , Risselada Herre Jelger 
Published: September 2022

AbstractProteins can specifically bind to curved membranes through curvature-induced hydrophobic lipid packing defects. The chemical diversity among such curvature ‘sensors’ challenges our understanding of how they differ from general membrane ‘binders’, that bind without curvature selectivity. Here, we combine an evolutionary algorithm with coarse-grained molecular dynamics simulations (Evo-MD) to resolve the peptide sequences that optimally recognize the curvature of lipid membranes. We subsequently demonstrate how a synergy between Evo-MD and a neural network (NN) can enhance the identification and discovery of curvature sensing peptides and proteins. To this aim, we benchmark a physics-trained NN model against experimental data and show that we can correctly identify known ‘sensors’ and ‘binders’. We illustrate that sensing and binding are in fact phenomena that lie on the same thermodynamic continuum, with only subtle but explainable differences in membrane binding free energy, consistent with the serendipitous discovery of sensors.TeaserAI-based design helps explain curvature-selective membrane binding behavior.