bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multimodal layer modelling revealsin-vivopathology in ALS
Authors: Northall Alicia , Doehler Juliane , Weber Miriam , Tellez Igor , Petri Susanne , Prudlo Johannes , Vielhaber Stefan , Schreiber Stefanie , Kuehn Esther 
Published: June 2023

AbstractAmyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterised by the loss of motor control. Current understanding of ALS pathology is largely based onpost-morteminvestigations at advanced disease stages. A systematicin-vivodescription of the microstructural changes that characterise early-stage ALS, and their subsequent development, is so far lacking.Recent advances in ultra-high field (7T) MRI data modelling allow us to investigate cortical layersin-vivo. Given the layer-specific and topographic signature of pathology in ALS, we combined submillimeter structural 7T-MRI data (qT1, QSM), functional localisers of body parts (upper limb, lower limb, face) and automated layer modelling to systematically describe pathology in the primary motor cortex (M1), in 12 living ALS-patients with reference to 12 age-, gender-, handedness- and education-matched controls. Longitudinal sampling was performed for a subset of patients. We calculated multimodal pathology maps for each layer (superficial layer, layer 5a, layer 5b, layer 6) of M1 to identify hotspots of demyelination, iron and calcium accumulation in different cortical fields.We show preserved mean cortical thickness and layer architectures of M1, despite significantly increased iron in layer 6 and significantly increased calcium in layer 5a and superficial layer, in patients compared to controls. The behaviorally first-affected cortical field shows significantly increased iron in L6 compared to other fields, while calcium accumulation is atopographic and significantly increased in the low-myelin borders between cortical fields compared to the fields themselves. A subset of patients with longitudinal data shows that the low-myelin borders are particularly disrupted, and that calcium hotspots but to a lesser extent iron hotspots precede demyelination. Finally, we highlight that a very-slow progressing patient (P4) shows a distinct pathology profile compared to the other patients.Our data shows that layer-specific markers ofin-vivopathology can be identified in ALS-patients with a single 7T-MRI measurement after first diagnosis, and that such data provide critical insights into the individual disease state. Our data highlight the non-topographic architecture of ALS disease spread, and the role of calcium rather than iron accumulation in predicting future demyelination. We also highlight a potentially important role of low-myelin borders, that are known to connect to multiple areas within the M1 architecture, in disease spread. Importantly, the distinct pathology profile of a very-slow progressing patient (P4) highlights a distinction between disease duration and pathology progression. Our findings demonstrate the importance ofin-vivohistology for the diagnosis and prognosis of neurodegenerative diseases such as ALS.
A Molecular Communication model for cellular metabolism
Authors: Sakkaff Zahmeeth , Freiburger Andrew P. , Catlett Jennie L. , Cashman Mikaela , Immaneni Aditya , Buan Nicole R. , Cohen Myra B. , Henry Christopher , Pierobon Massimiliano 
Published: June 2023

AbstractUnderstanding cellular engagement with its environment is essential to control and monitor metabolism. Molecular Communication theory (MC) offers a computational means to identify environmental perturbations that direct or signify cellular behaviors by quantifying the information about a molecular environment that is transmitted through a metabolic system. We developed an model that integrates conventional flux balance analysis metabolic modeling (FBA) and MC to mechanistically expand the scope of MC, and thereby uniquely blends mechanistic biology and information theory to understand how substrate consumption is captured reaction activity, metabolite excretion, and biomass growth. This is enabled by defining several channels through which environmental information transmits in a metabolic network. The information flow in bits that is calculated through this workflow further determines the maximal metabolic effect of environmental perturbations on cellular metabolism and behaviors, since FBA simulates maximal efficiency of the metabolic system. We exemplify this method on two intestinal symbionts –Bacteroides thetaiotaomicronandMethanobrevibacter smithii– and visually consolidated the results into constellation diagrams that facilitate interpretation of information flow from given environments and thereby cultivate the design of controllable biological systems. The unique confluence of metabolic modeling and information theory in this model advances basic understanding of cellular metabolism and has applied value for the Internet of Bio-Nano Things, synthetic biology, microbial ecology, and autonomous laboratories.
Comparative analysis of Respiratory Syncytial Virus frequency rates and viral load in different patient cohorts in a university hospital in Sao Paulo, Brazil, over an eight-year period (2005-2013)
Authors: de Souza Luna Luciano Kleber , Cruz Jessica Santiago , Souza Chaves Tânia do Socorro , Bellei Nancy 
Published: June 2023

AbstractRespiratory Syncytial Virus (RSV) poses a global health concern, particularly in young children, the elderly, and those immunosuppressed. RSV viral load is essential for understanding transmission, disease severity, prevention, and treatment. This retrospective study aimed to analyze the frequency rates and viral loads of RSV infections in different patient cohorts and age groups over an eight-year period in a university hospital in São Paulo, Brazil. This study analyzed 1380 immunocompetent (IC) and immunosuppressed (IS) patients with acute respiratory tract infections. IC included patients suspected of having severe acute respiratory syndrome caused by influenza A (H1N1)pdm09 virus (SARS H1N1), chronic heart disease (HD), and those receiving primary care service (PC). The IS comprised transplant patients and individuals with human immunodeficiency virus (HIV) infection. Respiratory samples were collected between 2005 and 2013. RSV detection and quantification were performed by RT-qPCR. Viral load was expressed as Log10 copies of RNA/mL. The overall RSV infection rate was 17.3%, with higher rates in children (23.9%) than in adults (12.9%), particularly in children under two years of age (28.2%). Children in the SARS H1N1 and PC subgroups had higher infection rates (16.4% and 34.9%, respectively), with the highest rate in PC children aged 1 to <2 years (45.45%). Adults with HD had a significantly higher frequency rate (27.83%) than those in the SARS H1N1 (2.65%) and IS (15.16%) subgroups. The RSV viral load ranged from 2.43 to 10.15 Log10 RNA copies/mL (mean ±SD = 5.82 ± 2.19). Hospitalized patients had significantly higher viral loads (7.34 ± 1.9) than outpatients (4.38 ± 1.89). Elderly bone marrow transplant patients also had significantly higher viral loads (7.57 ± 2.41) than younger adults (5.12 ± 1.87). This study provides insights into the patterns and impacts of RSV infection in different patient cohorts in Brazil, contributing to developing effective prevention, treatment, and control strategies. Further investigations are needed to understand the susceptibility and risk factors associated with RSV infection.
Identification of three distinct cell populations for urate excretion in human kidney
Authors: Sakaguchi Yoshihiko M. , Wiriyasermkul Pattama , Matsubayashi Masaya , Miyasaka Masaki , Sakaguchi Nau , Sahara Yoshiki , Takasato Minoru , Kinugawa Kaoru , Sugie Kazuma , Eriguchi Masahiro , Tsuruya Kazuhiko , Kuniyasu Hiroki , Nagamori Shushi , Mori Eiichiro 
Published: June 2023

AbstractIn humans, uric acid is an end-product of purine metabolism. Urate excretion from human kidney is tightly regulated by reabsorption and secretion. At least eleven genes have been identified as human renal urate transporters. However, it remains unclear whether all renal tubular cells express the same set of urate transporters. Here we show that renal tubular cells are divided into three distinct cell populations for urate handling. Analysis of healthy human kidneys at single-cell resolution revealed that not all renal tubular cells expressed the same set of urate transporters. Only 32% of renal tubular cells were related to both reabsorption and secretion, while the remaining renal tubular cells were related to either reabsorption or secretion, at 5% and 63% respectively. These results provide physiological insight into the molecular function of the transporters and renal urate handling on cell-units. Our findings also suggest that three different tubular cell populations cooperate to regulate urate excretion from human kidney.Highlight/Key pointsWe identified three distinct cell populations within the human renal anatomy that predict putative cellular transport mode, and our findings indicate cellular inhomogeneity with distinct roles such as urate secretion and reabsorption.Our model of physiological urate handling demonstrates the excretion dynamics in human kidney in terms of single cell-units.Our cellular urate transport analyses suggest the reversibility of some urate transporters even in certain physiological conditions.The physiological function of SLC2A9 is not limited to urate reabsorption; it is also involved in urate secretion restriction.This methodology can be applied to investigations of transport mechanisms in general, regardless of epithelial cell types, species, and substrates.
Comprehensive Assessment of Elevende novoHiFi Assemblers on Complex Eukaryotic Genomes and Metagenomes
Authors: Yu Wenjuan , Luo Haohui , Yang Jinbao , Zhang Shengchen , Jiang Heling , Zhao Xianjia , Hui Xingqi , Sun Da , Li Liang , Wei Xiu-qing , Lonardi Stefano , Pan Weihua 
Published: June 2023

ABSTRACTBackgroundPacific Bioscience HiFi sequencing technology generates long reads (>10 kbp) with very high accuracy (less than 0.01% sequencing error). While severalde novoassembly tools are available for HiFi reads, there are no comprehensive studies on the evaluation of these assemblers.ResultsWe evaluated the performance of elevende novoHiFi assemblers on (i) real data for three eukaryotic genomes, (ii) 34 synthetic datasets with different ploidy, sequencing coverage levels, heterozygosity rates and sequencing error rates, (iii) one real metagenomic dataset, and (iv) five synthetic metagenomic datasets with different composition abundance and heterozygosity rates. The nine assemblers were evaluated using QUAST (Quality Assessment Tool) and BUSCO (Benchmarking Universal Single-Copy Ortholog). We also used several additional criteria, namely, completion rate, single-copy completion rate, duplicated completion rate, average proportion of largest category, average distance difference, quality value, run-time and memory utilization. On complex eukaryotic genomes, Hifiasm had a clear advantage over the other assemblers in all tested experiments. On synthetic datasets, Hifiasm, HiCanu, and HiFlye performed equally well. Shasta and Peregrine had good performance across varying ploidy, but required high computational resources. On metagenomic datasets, Hifiasm-meta demonstrated a clear advantage over other assemblers.ConclusionWe carried out a comprehensive benchmarking study of commonly used assemblers on complex eukaryotic genomes and metagenomes. Our study will help the research community to choose the most appropriate assembler for their data and identify possible improvements in assembly algorithms.
Epistasis Arises from Shifting the Rate-Limiting Step during Enzyme Evolution
Authors: Fröhlich Christopher , Bunzel H. Adrian , Buda Karol , Mulholland Adrian J. , van der Kamp Marc W. , Johnsen Pål J. , Leiros Hanna-Kirsti S. , Tokuriki Nobuhiko 
Published: June 2023

ABSTRACTThe molecular mechanisms by which epistasis boosts enzyme activity remain elusive, undermining our ability to predict the evolution of pathogens and engineer novel biocatalysts. Here, we reveal how directed evolution of a β-lactamase yielded highly epistatic activity enhancements. Evolution selected four mutations that increase antibiotic resistance 40-fold, despite their marginal individual effects (≤ 2-fold). Synergistic improvements coincided with the introduction of super-stochiometric burst kinetics, indicating that epistasis is rooted in the enzyme’s conformational dynamics. Kinetic, structural, and dynamical analyses reveal that epistasis was driven by distinct effects of each mutation on the catalytic cycle. The first mutation acquired during evolution increases protein flexibility and accelerates substrate binding, which is rate-limiting in the wild-type enzyme. The ensuing mutations predominantly boosted the chemical steps by fine-tuning substrate interactions. Our work identifies an overlooked cause for epistasis: changing the rate-limiting step can result in substantial positive synergy boosting enzyme activity.
The super-healing MRL strain promotes muscle growth in muscular dystrophy through a regenerative extracellular matrix
Authors: O’Brien Joseph G. , Willis Alexander B. , Long Ashlee M. , Kwon Jason , Lee GaHyun , Li Frank , Page Patrick G.T. , Vo Andy H. , Hadhazy Michele , Crosbie Rachelle H. , Demonbreun Alexis R. , McNally Elizabeth M. 
Published: June 2023

ABSTRACTGenetic background shifts the severity of muscular dystrophy. In mice, the DBA/2J strain confers a more severe muscular dystrophy phenotype, whereas the Murphy’s Roth Large (MRL) strain has “super-healing” properties that reduce fibrosis. A comparative analysis of theSgcgnull model of Limb Girdle Muscular Dystrophy in the DBA/2J versus MRL strain showed the MRL background was associated with greater myofiber regeneration and reduced structural degradation of muscle. Transcriptomic profiling of dystrophic muscle in the DBA/2J and MRL strains indicated strain-dependent expression of the extracellular matrix (ECM) and TGF-β signaling genes. To investigate the MRL ECM, cellular components were removed from dystrophic muscle sections to generate decellularized “myoscaffolds”. Decellularized myoscaffolds from dystrophic mice in the protective MRL strain had significantly less deposition of collagen and matrix-bound TGF-β1 and TGF-β3 throughout the matrix, and dystrophic myoscaffolds from the MRL background were enriched in myokines. C2C12 myoblasts were seeded onto decellularized matrices fromSgcg−/−MRL andSgcg−/−DBA/2J matrices. Acellular myoscaffolds from the dystrophic MRL background induced myoblast differentiation and growth compared to dystrophic myoscaffolds from the DBA/2J matrices. These studies establish that the MRL background also generates its effect through a highly regenerative ECM, which is active even in muscular dystrophy.Brief SummaryThe extracellular matrix of the super-healing MRL mouse strain harbors regenerative myokines that improve skeletal muscle growth and function in muscular dystrophy.Graphical Abstract
A Platform for Controlled Template-Independent Enzymatic Synthesis of RNA Oligonucleotides and Therapeutics
Authors: Wiegand Daniel J. , Rittichier Jonathan , Meyer Ella , Lee Howon , Conway Nicholas J. , Ahlstedt Daniel , Yurtsever Zeynep , Rainone Dominic , Kuru Erkin , Church George M. 
Published: June 2023

AbstractTherapeutic RNA oligonucleotides have shown tremendous potential to manage and treat disease, yet current manufacturing methods cannot deliver on this promise. Here, we report the development and optimization of a novel, aqueous-based, template-independent enzymatic RNA oligonucleotide synthesis platform as an alternative to traditional chemical methodologies. Our platform is made possible by reversible terminator nucleoside triphosphates and an enzyme capable of their incorporation. We show that many common therapeutic RNA modifications are compatible with our process and demonstrate the enzymatic synthesis of natural and modified oligonucleotides in both liquid and solid phases. Our platform offers many unique advantages over chemical synthesis, including the realization of a more sustainable process to produce therapeutic RNA oligonucleotides.One-Sentence SummaryAn enzyme and novel nucleotide building blocks are used to synthesize RNA oligonucleotides template independently under aqueous conditions.
Matrix stiffening promotes perinuclear clustering of mitochondria
Authors: Daga Piyush , Thurakkal Basil , Rawal Simran , Das Tamal 
Published: June 2023

ABSTRACTMechanical cues from the tissue microenvironment, such as the stiffness of the extracellular matrix, modulate cellular forms and functions. As numerous studies have shown, this modulation depends on the stiffness-dependent remodeling of cytoskeletal elements. In contrast, very little is known about how the intracellular organelles such as mitochondria respond to matrix stiffness and whether their form, function, and localization change accordingly. Here, we performed an extensive quantitative characterization of mitochondrial morphology, subcellular localization, dynamics and membrane tension on soft and stiff matrices. This characterization revealed that while matrix stiffness affected all these aspects, matrix stiffening most distinctively led to an increased perinuclear clustering of mitochondria. Subsequently, we could identify the matrix stiffness-sensitive perinuclear localization of filamin as the key factor dictating this perinuclear clustering. Photo-conversion labeling and fluorescent recovery after photobleaching experiments revealed that perinuclear and peripheral mitochondrial populations differed in their motility on the soft matrix but surprisingly they did not show any difference on the stiff matrix. Finally, perinuclear mitochondrial clustering appeared to be crucial for priming human mesenchymal stem cells towards osteogenesis on the stiff matrix. Taken together, we elucidate a dependence of mitochondrial localization on matrix stiffness, which possibly enables a cell to adapt to its microenvironment.
Synthesis and new evidence from the PROTECT UK National Core Study: Determining occupational risks of SARS-CoV-2 infection and COVID-19 mortality
Authors: Rhodes S , Beale S , Cherrie M , Mueller W , Holland F , Matz M , Basinas I , Wilkinson J , Gittins M , Farrell B , Hayward A , Pearce N , van Tongeren M 
Published: June 2023

AbstractIntroductionThe PROTECT National Core Study was funded by the UK Health and Safety Executive (HSE) to investigate routes of transmission for SARS-CoV-2 and variation between settings.MethodsA workshop was organised in Oct 2022.We brought together evidence from five published epidemiological studies that compared risks of SARS-CoV-2 infection or COVID-19 mortality by occupation or sector funded by PROTECT relating to three non-overlapping data sets, plus additional unpublished analyses relating to the Omicron period. We extracted descriptive study level data and model results. We investigated risk across four pandemic waves using forest plots for key occupational groups by time-period.ResultsResults were largely consistent across different studies with different expected biases. Healthcare and social care sectors saw elevated risks of SARS-CoV-2 infection and COVID-19 mortality early in the pandemic, but thereafter this declined and varied by specific occupational subgroup. The education sector saw sustained elevated risks of infection after the initial lockdown period with little evidence of elevated mortality.ConclusionsIncreased in risk of infection and mortality were consistently observed for occupations in high risk sectors particularly during the early stage of the pandemic. The education sector showed a different pattern compared to the other high risk sectors, as relative risk of infections remained high in the later phased of the pandemic, although no increased in COVID-19 mortality (compared to low-risk occupations) was observed in this sector in any point during the pandemic.
Identifying multi-resolution clusters of diseases in ten million patients with multimorbidity in primary care in England
Authors: Beaney Thomas , Clarke Jonathan , Salman David , Woodcock Thomas , Majeed Azeem , Aylin Paul , Barahona Mauricio 
Published: June 2023

AbstractIdentifying clusters of co-occurring diseases can aid understanding of shared aetiology, management of co-morbidities, and the discovery of new disease associations. Here, we use data from a population of over ten million people with multimorbidity registered to primary care in England to identify disease clusters through a two-stage process. First, we extract data-driven representations of 212 diseases from patient records employing i) co-occurrence-based methods and ii) sequence-based natural language processing methods. Second, we apply multiscale graph-based clustering to identify clusters based on disease similarity at multiple resolutions, which outperforms k-means and hierarchical clustering in explaining known disease associations. We find that diseases display an almost-hierarchical structure across resolutions from closely to more loosely similar co-occurrence patterns and identify interpretable clusters corresponding to both established and novel patterns. Our method provides a tool for clustering diseases at different levels of resolution from co-occurrence patterns in high-dimensional electronic healthcare record data.
Structure and replication cycle of a virus infecting climate-modulating algaEmiliania huxleyi
Authors: Homola Miroslav , Büttner Carina R. , Füzik Tibor , Křepelka Pavel , Holbová Radka , Nováček Jiří , Chaillet Marten , Förster Friedrich , Wilson William H. , Schroeder Declan C. , Plevka Pavel 
Published: June 2023

AbstractThe globally distributed marine algaEmiliania huxleyiproduces reflective calcite disks (coccoliths) that increase the albedo of ocean water and thus reduce the heat absorption in the ocean, which cools the Earth’s climate. The population density ofE. huxleyiis restricted by nucleocytoplasmic large DNA viruses, includingE. huxleyivirus 201 (EhV-201). Despite the impact ofE. huxleyiviruses on the climate, there is limited information about their structure and replication. Here we show that the dsDNA genome inside the EhV-201 virion is protected by an inner membrane, capsid, and outer membrane decorated with numerous transmembrane proteins. The virions are prone to deformation, and parts of their capsids deviate from the icosahedral arrangement. EhV-201 virions infectE. huxleyiby using their fivefold vertex to bind to a host cell and fuse the virus’s inner membrane with the plasma membrane. Whereas the replication of EhV-201 probably occurs in the nucleus, virions assemble in the cytoplasm at the surface of endoplasmic reticulum-derived membrane segments. Genome packaging initiates synchronously with the capsid assembly and completes through an aperture in the forming capsid. Upon the completion of genome packaging, the capsids change conformation, which enables them to acquire an outer membrane by budding into intracellular vesicles. EhV-201 infection induces a loss of surface protective layers fromE. huxleyicells, which allows the continuous release of virions by exocytosis. Our results provide insight into how EhVs bypass the surface protective layers ofE. huxleyiand exploit the organelles of an infected cell for progeny assembly.