bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enrichment of colibactin-associated mutational signatures in unexplained colorectal polyposis patients
Authors: Terlouw D. , Boot A. , Ducarmon Q. R. , Nooij S. , Suerink M. , van Leerdam M.E. , van Egmond D. , Tops C.M. , Zwittink R. D. , Ruano D. , Langers A.M.J. , Nielsen M. , van Wezel T. , Morreau H. 
Published: June 2023

AbstractColibactin, a genotoxin produced by polyketide synthase harboring (pks+) bacteria, induces double-strand breaks and chromosome aberrations. Consequently, enrichment ofpks+Escherichia coliin colorectal cancer and polyposis suggests a possible carcinogenic effect in the large intestine. Additionally, specific colibactin-associated mutational signatures; SBS88 and ID18 in the Catalogue of Somatic Mutations in Cancer database, are detected in colorectal carcinomas. Previous research showed that a recurrentAPCsplice variant perfectly fits SBS88. In this study, we explore the presence of colibactin-associated signatures and fecalpksin an unexplained polyposis cohort. Somatic targeted Next-Generation Sequencing (NGS) was performed for 379 patients. Additionally, for a subset of 29 patients, metagenomics was performed on feces and mutational signature analyses using Whole-Genome Sequencing (WGS) on Formalin-Fixed Paraffin Embedded (FFPE) colorectal tissue blocks. NGS showed somaticAPCvariants fitting SBS88 or ID18 in at least one colorectal adenoma or carcinoma in 29% of patients. Fecal metagenomic analyses revealed enriched presence ofpksgenes in patients with somatic variants fitting colibactin-associated signatures compared to patients without variants fitting colibactin-associated signatures. Also, mutational signature analyses showed enrichment of SBS88 and ID18 in patients with variants fitting these signatures in NGS compared to patients without. These findings further support colibactins ability to mutagenize colorectal mucosa and contribute to the development of colorectal adenomas and carcinomas explaining a relevant part of patients with unexplained polyposis.
Accurate neural control of a hand prosthesis by posture-related activity in the primate grasping circuit
Authors: Agudelo-Toro Andres , Michaels Jonathan A. , Sheng Wei-An , Scherberger Hansjörg 
Published: June 2023

SummaryBrain-computer interfaces (BCIs) have the potential to restore hand movement for people with paralysis, but current devices still lack the fine control required to interact with objects of daily living. Following understanding of cortical activity during arm reaches, hand BCI studies have focused on velocity control. However, mounting evidence suggests that posture, and not velocity, dominates in hand-related areas during natural movement. To explore whether this signal can causally control a prosthesis, we developed a novel BCI training paradigm centered on the reproduction of hand posture transitions. Macaque monkeys trained with the protocol were able to control a multi-dimensional hand prosthesis at high-accuracy, including execution of the very intricate precision grip. Subsequent analysis revealed that the posture signal in the target grasping areas was a major contributor to control. Population activity exhibited pattern separation and dimensionality increases driven by posture kinematics, and simulations with a grasping circuit model demonstrated the generalizability of our approach. We present for the first time neural posture control of a multi-dimensional hand prosthesis, opening the door for future devices to leverage this additional information channel.
Narrow-window DIA: Ultra-fast quantitative analysis of comprehensive proteomes with high sequencing depth
Authors: Guzman Ulises H , Martinez Del Val Ana , Ye Zilu , Damoc Eugen , Arrey Tabiwang N. , Pashkova Anna , Denisov Eduard , Petzoldt Johannes , Peterson Amelia C. , Harking Florian , Østergaard Ole , Stewart Hamish , Xuan Yue , Hermanson Daniel , Hock Christian , Makarov Alexander , Zabrouskov Vlad , Olsen Jesper V. 
Published: June 2023

AbstractMass spectrometry (MS)-based proteomics aims to characterize comprehensive proteomes in a fast and reproducible manner. Here, we present an ultra-fast scanning data-independent acquisition (DIA) strategy consisting on 2-Th precursor isolation windows, dissolving the differences between data-dependent and independent methods. This is achieved by pairing a Quadrupole Orbitrap mass spectrometer with the asymmetric track lossless (Astral) analyzer that provides >200 Hz MS/MS scanning speed, high resolving power and sensitivity, as well as low ppm-mass accuracy. Narrow-window DIA enables profiling of up to 100 full yeast proteomes per day, or ∼10,000 human proteins in half-an-hour. Moreover, multi-shot acquisition of fractionated samples allows comprehensive coverage of human proteomes in ∼3h, showing comparable depth to next-generation RNA sequencing and with 10x higher throughput compared to current state-of-the-art MS. High quantitative precision and accuracy is demonstrated with high peptide coverage in a 3-species proteome mixture, quantifying 14,000+ proteins in a single run in half-an-hour.TeaserAccurate and precise label-free quantification with comprehensive proteome coverage using narrow-window DIA
Ultrasonographic measurements of fascicle length overestimate adaptations in serial sarcomere number
Authors: Hinks Avery , Franchi Martino , Power Geoffrey A. 
Published: June 2023

AbstractUltrasound-derived measurements of muscle fascicle length (FL) are often used to infer increases (chronic stretch or training) or decreases (muscle disuse or aging) in serial sarcomere number (SSN). Whether FL adaptations measured via ultrasound can truly approximate SSN adaptations has not been investigated. We casted the right hindlimb of 15 male Sprague-Dawley rats in a dorsiflexed position (i.e., stretched the plantar flexors) for 2 weeks, with the left hindlimb serving as a control. Ultrasound images of the soleus, lateral gastrocnemius (LG), and medial gastrocnemius (MG) were obtained with the ankle at 90° and full dorsiflexion for both hindlimbs pre and post-cast. Following post-cast ultrasound measurements, legs were fixed in formalin with the ankle at 90°, then muscles were dissected, and fascicles were teased out for measurement of sarcomere lengths via laser diffraction and calculation of SSN. Ultrasound detected an 11% increase in soleus FL, a 12% decrease in LG FL, and an 8-11% increase in MG FL for proximal fascicles and at full dorsiflexion. These adaptations were partly reflected by SSN adaptations, with a 6% greater soleus SSN in the casted leg than the un-casted leg, but no SSN differences for the gastrocnemii. Weak relationships were observed between ultrasonographic measurements of FL and measurements of FL and SSN from dissected fascicles. Our results showed that ultrasound-derived FL measurements can overestimate an increase in SSN by ∼5%. Future studies should be cautious when concluding a large magnitude of sarcomerogenesis from ultrasound-derived FL measurements, and may consider applying a correction factor.Key Points SummaryMeasurements of muscle fascicle length via ultrasound are often used to infer changes in serial sarcomere number, such as increases following chronic stretch or resistance training, and decreases with aging or muscle disuseThe present study used a rat model of casting the plantar flexor muscles in a stretched position to investigate directly whether ultrasound-derived fascicle length can accurately detect adaptations in serial sarcomere numberUltrasound detected an ∼11% increase in soleus fascicle length, but measurements on dissected fascicles showed the actual increase in serial sarcomere number was only ∼6%; therefore, measurements of ultrasound-derived fascicle length can overestimate serial sarcomere number adaptations by as much as 5%
Quantitative Analysis of the Optogenetic Excitability of CA1 Neurons
Authors: Schoeters Ruben , Tarnaud Thomas , Weyn Laila , Joseph Wout , Raedt Robrecht , Tanghe Emmeric 
Published: June 2023

AbstractOptogenetics has emerged as a promising technique for modulating neuronal activity and holds potential for the treatment of neurological disorders such as temporal lobe epilepsy (TLE). However, clinical translation still faces many challenges. This in-silico study aims to enhance the understanding of optogenetic excitability in CA1 cells and to identify strategies for improving stimulation protocols. Employing state-of-the-art computational models, the optogenetic excitability of four CA1 cells, two pyramidal and two interneurons, expressing ChR2(H134R) is investigated. The results demonstrate that confining the opsin to specific neuronal membrane compartments significantly improves excitability. An improvement is also achieved by focusing the light beam on the most excitable cell region. Moreover, the perpendicular orientation of the optical fiber relative to the somato-dendritic axis yields superior results. Inter-cell variability is observed, highlighting the importance of considering neuron degeneracy when designing optogenetic tools. Opsin confinement to the basal dendrites of the pyramidal cells renders the neuron the most excitability. A global sensitivity analysis identified opsin location and expression level as having the greatest impact on simulation outcomes. The error reduction of simulation outcome due to coupling of neuron modeling with light propagation is shown. The results promote spatial confinement and increased opsin expression levels as important improvement strategies. On the other hand, uncertainties in these parameters limit precise determination of the irradiance thresholds. This study provides valuable insights on optogenetic excitability of CA1 cells useful for the development of improved optogenetic stimulation protocols for, for instance, TLE treatment.
Perivascular spaces in Alzheimer’s disease are associated with inflammatory, stress-related, and hypertension biomarkers
Authors: Sibilia Francesca , Sheikh-Bahaei Nasim , Mack Wendy J. , Choupan Jeiran 
Published: June 2023

AbstractPerivascular spaces (PVS) are fluid-filled spaces surrounding the brain vasculature. Literature suggests that PVS may play a significant role in aging and neurological disorders, including Alzheimer’s disease (AD).Cortisol, a stress hormone, has been implicated in the development and progression of AD. Hypertension, a common condition in older adults, has been found to be a risk factor for AD. Hypertension may contribute to PVS enlargement, impairing the clearance of waste products from the brain and promoting neuroinflammation. This study aims to understand the potential interactions between PVS, cortisol, hypertension, and inflammation in the context of cognitive impairment.Using MRI scans acquired at 1.5T, PVS were quantified in a cohort of 465 individuals with cognitive impairment. PVS was calculated in the basal ganglia and centrum semiovale using an automated segmentation approach. Levels of cortisol and angiotensin-converting enzyme (ACE) (an indicator of hypertension) were measured from plasma. Inflammatory biomarkers, such as cytokines and matrix metalloproteinases, were analyzed using advanced laboratory techniques.Main effect and interaction analyses were performed to examine the associations between PVS severity, cortisol levels, hypertension, and inflammatory biomarkers.In the centrum semiovale, higher levels of inflammation reduced cortisol associations with PVS volume fraction.For ACE, an inverse association with PVS was seen only when interacting with TNFr2 (a transmembrane receptor of TNF). There was also a significant inverse main effect of TNFr2.In the PVS basal ganglia, a significant positive association was found with TRAIL (a TNF receptor inducing apoptosis).These findings show for the first time the intricate relationships between PVS structure and the levels of stress-related, hypertension, and inflammatory biomarkers. This research could potentially guide future studies regarding the underlying mechanisms of AD pathogenesis and the potential development of novel therapeutic strategies targeting these inflammation factors.
Functionally and metabolically divergent melanoma-associated macrophages originate from common bone-marrow precursors
Authors: Pizzurro Gabriela A. , Bridges Kate , Jiang Xiaodong , Vidyarthi Aurobind , Miller-Jensen Kathryn , Colegio Oscar R. 
Published: June 2023

AbstractMelanomas display high numbers of tumor-associated macrophages (TAMs), which correlate with worse prognosis. Harnessing macrophages for therapeutic purposes has been particularly challenging due to their heterogeneity, based on their ontogeny and function and driven by the tissue-specific niche. In the present study, we used the YUMM1.7 model to better understand melanoma TAM origin and dynamics during tumor progression, with potential therapeutic implications. We identified distinct TAM subsets based on F4/80 expression, with the F4/80highfraction increasing over time and displaying tissue-resident-like phenotype. While skin-resident macrophages showed mixed on-togeny, F4/80+TAM subsets in i.d. YUMM1.7 tumors originated almost exclusively from bone-marrow precursors. Mul-tiparametric analysis of macrophage phenotype showed a temporal divergence of F4/80+TAM subpopulations, which also differed from skin-resident subsets, and from their monocytic precursors. Overall, F4/80+TAMs displayed co-ex-pression of M1- and M2-like canonical markers, while RNA-seq and pathway analysis showed differential immunosup-pressive and metabolic profiles. GSEA showed F4/80highTAMs to rely on oxidative phosphorylation, with increased proliferation and protein secretion while F4/80lowcells had high pro-inflammatory and intracellular signaling pathways, with lipid and polyamine metabolism. Overall, the present in-depth characterization provides further evidence of the ontogeny of the evolving melanoma TAMs, whose gene expression profiles matched recently-identified TAM clusters in other tumor models and human cancers. These findings provide evidence for potentially targeting specific immunosup-pressive TAMs in advanced tumor stages.
What fraction of cellular DNA turnover becomes cfDNA?
Authors: Sender Ron , Noor Elad , Milo Ron , Dor Yuval 
Published: June 2023

AbstractCell-free DNA (cfDNA) tests use small amounts of DNA in the bloodstream as biomarkers. While it is thought that cfDNA is largely released by dying cells, the proportion of dying cells’ DNA that reaches the bloodstream is unknown. Here, we integrate estimates of cellular turnover rates to calculate the expected amount of cfDNA. By comparing this to the actual amount of cell type-specific cfDNA, we estimate the proportion of DNA reaching plasma as cfDNA. We demonstrate that <10% of the DNA from dying cells is detectable in plasma, and the ratios of measured to expected cfDNA levels vary a thousand-fold among cell types, often reaching well below 0.1%. The analysis suggests that local clearance, presumably via phagocytosis, takes up most of the dying cells’ DNA. Insights into the underlying mechanism may help to understand the physiological significance of cfDNA and improve the sensitivity of liquid biopsies.
Functional identification of soluble uric acid as an endogenous inhibitor of CD38
Authors: Wen Shijie , Arakawa Hiroshi , Yokoyama Shigeru , Shirasaka Yoshiyuki , Higashida Haruhiro , Tamai Ikumi 
Published: June 2023

AbstractExcessive elevation or reduction of soluble uric acid (sUA) levels has been linked to some of pathological states, raising another subject that sUA at physiological levels may be essential for the maintenance of health. Yet, the fundamental physiological functions and molecular targets of sUA remain largely unknown. Using enzyme assays andin vitroandin vivometabolic assays, we demonstrate that sUA directly inhibits the hydrolase and cyclase activities of CD38 via a reversible non-competitive mechanism, thereby limiting nicotinamide adenine dinucleotide (NAD+) degradation. CD38 inhibition is restricted to sUA in purine metabolism, and a structural comparison using methyl analogs of sUA such as caffeine metabolites shows that 1,3-dihydroimidazol-2-one is the main functional group. Moreover, sUA at physiological levels prevents crude lipopolysaccharide (cLPS)-induced systemic inflammation and monosodium urate (MSU) crystal-induced peritonitis in mice by interacting with CD38. Together, this study unveils an unexpected physiological role for sUA in controlling NAD+availability and innate immunity through CD38 inhibition, providing a new perspective on sUA homeostasis and purine metabolism.
A hypothetical intervention to reduce inequities in anxiety for Multiracial people: simulating an intervention on childhood adversity
Authors: Lam-Hine Tracy , Bradshaw Patrick T. , Allen Amani M. , Omi Michael , Riddell Corinne A. 
Published: June 2023

AbstractMultiracial people report higher mean Adverse Childhood Experiences (ACEs) scores and prevalence of anxiety than other racial groups. Studies using statistical interactions to estimate racial differences in ACEs-anxiety associations do not show stronger associations for Multiracial people. Using data from Waves 1 (1995-97) through 4 (2008-09) of the National Longitudinal Study of Adolescent to Adult Health (Add Health), we simulated a stochastic intervention over 1,000 resampled datasets to estimate the race-specific cases averted per 1,000 of anxiety if all racial groups had the same exposure distribution of ACEs as Whites. Simulated cases averted were greatest for the Multiracial group, (median = -4.17 cases per 1,000, 95% CI: -7.42, -1.86). The model also predicted smaller risk reductions for Black participants (-0.76, 95% CI: -1.53, -0.19). CIs around estimates for other racial groups included the null. An intervention to reduce racial disparities in exposure to ACEs could help reduce the inequitable burden of anxiety on the Multiracial population. Stochastic methods support consequentialist approaches to racial health equity, and can encourage greater dialogue between public health researchers, policymakers, and practitioners.
Ethical considerations related to drone use for environment and health research: a scoping review protocol
Authors: Hoek Spaans Remy , Drumond Bruna , van Daalen Kim , Derbyshire Alison , Da Silva Adriano , Lana Raquel Martins , Vega Mauricio Santos , Carrasco-Escobar Gabriel , Codeço Claudia , Lowe Rachel 
Published: June 2023

AbstractIntroductionThe use of drones in environment and health research is a relatively new phenomenon. A principal research activity drones are used for is environmental monitoring, which can raise concerns in local communities. Existing ethical guidance for researchers is often not specific to drone technology and practices vary between research settings. Therefore, this scoping review aims to gather the evidence available on how the use of drones is perceived by local communities, as well as current research practices, and ethical guidance related to drone deployment.Methods and analysisThis scoping review will follow the PRISMA-ScR and the Joana Briggs Institute guidelines. The literature search will be conducted using academic databases and grey literature sources. After pilot testing the inclusion criteria and data extraction tool, two researchers will double-screen and then chart available evidence independently. A content analysis will be carried out to identify patterns of categories or terms used to describe ethical considerations related to drone usage for environmental monitoring in the literature using the R Package RQDA. Discrepancies in any phase of the project are solved through consensus.Ethics and disseminationEthical approval is not required; only secondary data will be used. This protocol is registered on the Open Science Framework (osf.io/a78et). The results will be disseminated through publication in a scientific journal and will be used to inform drone field campaigns in the Wellcome Trust funded HARMONIZE project. HARMONIZE aims to develop cost-effective and reproducible digital infrastructure for stakeholders in climate change hotspots in Latin America & the Caribbean and will use drone technology to collect data on fine scale landscape changes.
Conditional lethality profiling reveals anticancer mechanisms of action and drug-nutrient interactions
Authors: Flickinger Kyle M. , Wilson Kelli M. , Rossiter Nicholas J. , Hunger Andrea L. , Lee Tobie D. , Hall Matthew D. , Cantor Jason R. 
Published: June 2023

SUMMARYChemical screening studies have identified drug sensitivities across hundreds of cancer cell lines but most putative therapeutics fail to translate. Discovery and development of drug candidates in models that more accurately reflect nutrient availability in human biofluids may help in addressing this major challenge. Here we performed high-throughput screens in conventional versus Human Plasma-Like Medium (HPLM). Sets of conditional anticancer compounds span phases of clinical development and include non-oncology drugs. Among these, we characterize a unique dual-mechanism of action for brivudine, an agent otherwise approved for antiviral treatment. Using an integrative approach, we find that brivudine affects two independent targets in folate metabolism. We also traced conditional phenotypes for several drugs to the availability of nucleotide salvage pathway substrates and verified others for compounds that seemingly elicit off-target anticancer effects. Our findings establish generalizable strategies for exploiting conditional lethality in HPLM to reveal therapeutic candidates and mechanisms of action.
Population age and household structures shape transmission dynamics of emerging infectious diseases: a longitudinal microsimulation approach
Authors: Møgelmose Signe , Vijnck Laurens , Neven Frank , Neels Karel , Beutels Philippe , Hens Niel 
Published: June 2023

AbstractHost population demographics and patterns of host-to-host interactions are important drivers of heterogeneity in infectious disease transmission. To improve our understanding of how population structures and changes therein influence disease transmission dynamics at the individual and population level, we model a dynamic age-and household-structured population using longitudinal microdata drawn from Belgian census and population registers. At different points in time, we simulate the spread of a close-contact infectious disease and vary the age profiles of infectiousness and susceptibility to reflect specific infections (e.g. influenza and SARS-CoV-2) using a two-level mixing model, which distinguishes between exposure to infection in the household and exposure in the community. We find a strong relationship between age and household structures, which, in combination with social mixing patterns and epidemiological parameters, shape the spread of an emerging infection. Disease transmission in the adult population in particular is explained by differential household compositions and not just household size. Moreover, we highlight how demographic processes alter population structures in an ageing population and how these in turn affect disease transmission dynamics across population groups.