bluuebunny/crossref_metadata_2025 huggingface dataset:
AN UNKNOWN TRIBUTE BY FARINELLI TO KING PHILIP V OF SPAIN
Authors: TUFANO LUCIO
Published: August 2021

Carlo Broschi, better known as Farinelli, arrived in Madrid on 7 August 1737. King Philip V and his wife Elisabeth Farnese were deeply impressed by his vocal qualities and invited him to remain in their service, on extremely rewarding terms. Although few sources concerning his first months in Spain are available, a newly discovered libretto, L'ombra di Luigi XIV il Grande, sheds light on his position at the Spanish court and his response to the privileged situation he enjoyed. The work is a short solo cantata commissioned by Farinelli and offered to Philip V for his name day in 1738. The title-page indicates Francesco Feo as the composer, but no sources for the musical setting have yet been located, nor any information about a performance of the work. This article examines the content of the cantata's text and situates it within what is known about the life of Farinelli. It also reconstructs in detail the literary career of the author of the text, Giuseppe di Rosa, who was also a magistrate and historian. Additionally, it links the genesis of this encomiastic piece with the activity of Giovanni Battista Filomarino, Neapolitan ambassador at the court of Madrid.
Using Meteorite Magnetism to Understand the History of Our Solar System: A Decade of Progress and Upcoming Challenges
Authors: Nichols Claire I. O.
Published: August 2021

Key Points

High spatial and magnetic moment sensitivity microscopy techniques have revolutionized meteorite paleomagnetism in the last decade

Fu et al. (2021) used quantum diamond microscopy to reinterpret the magnetization of Allende with implications for the protoplanetary disk

Further work is required to interpret extraterrestrial paleomagnetic remanences, and how to recover reliable paleointensity estimates
Multicellular Algae Discovered in an Early Cambrian Formation
Authors: Shultz David
Published: August 2021

A new study describes eukaryotic organisms found organized in a cortex-medulla pattern in southern China’s Kuanchuanpu Formation.
Investigating the Coupled Magnetosphere‐Ionosphere‐Thermosphere (M‐I‐T) System's Responses to the 20 November 2003 Superstorm
Authors: Horvath Ildiko , Lovell Brian C.
Published: August 2021

Utilizing multi‐satellite/instrument observations, we investigate the November 20 2003 Superstorm's impacts on the forward fountain, the duskside and dawnside subauroral flows, and the chemical makeup of the ionospheric plasma. New results show that the nightside forward fountain became active before local midnight and soon after the interplanetary magnetic field (IMF) turned southward at ∼12 UT and remained active for the rest of 20 November and early 21 November. The fountain‐related strong equatorial upward E × B drift lifted up the F2 layer above ∼391 km altitude creating low plasma densities at equatorial and low latitudes. In both hemispheres, the large convection and subauroral electric (E) fields drove plasmaspheric erosions eroding the mid‐ and high‐latitude ionosphere poleward of the plasmapause. On the duskside and dawnside, the subauroral E field drove the Subauroral Polarization Streams (SAPS) in the sunward direction. As our southern cases show, the SAPS E field changed the ionospheric plasma's chemical makeup by locally enhancing the NO+ content and thus decreasing the O/N2 content associated with depleted plasma densities. We conclude that in the strongly coupled Magnetosphere‐Ionosphere‐Thermosphere system, the plasmaspheric erosion had a primary role in depleting the ionospheric plasma. Furthermore, the solar wind pressure disturbances during the long‐lasting southward IMF orientation led to the development of conjugate duskside and dawnside sunward SAPS flows, and SAPS flows contributed to the ionospheric plasma's depletion by increasing the NO+ content as our southern cases show. For the first time, correlated multi‐satellite observations show the dawnside sunward SAPS flows in latitudes and in longitudes.
Planetary Period Oscillations of Saturn’s Dayside Equatorial Ionospheric Electron Density Observed on Cassini’s Proximal Passes
Authors: Provan G. , Cowley S. W. H. , Bunce E. J. , Milan S. E. , Persoon A. M. , Gurnett D. A.
Published: August 2021

We examine electron density data obtained in Saturn’s dayside equatorial ionosphere during Cassini’s proximal periapsis passes, specifically data derived from wave spectra, for evidence of modulation with the planetary period oscillations (PPOs) observed ubiquitously throughout Saturn’s magnetosphere. Clear evidence is found on northern hemisphere inbound passes where northern system modulations occur in the ionospheric diffusive layer peaking at a factor of ∼7 at ∼3,200 km altitude, extending at lesser factors to ∼7,000 km altitude in the transport region. Simultaneous southern system modulations by factors ∼1.5–2.5 are also found above ∼3,400 km. Factor of ∼4–10 northern system modulations are also detected in the diffusive layer and transport regions to ∼6,000 km in the outbound pass data, though southern system modulations were not clearly discerned within the data scatter. Modulations were not detected in the photochemical equilibrium layer at altitudes ∼1,600–2,200 km. Where clear modulations were observed, their phases in the diffusive layer were close to those of the principal PPO meridians (determined previously from near‐apoapsis nightside magnetic data) for both systems, moving to somewhat earlier PPO phases by a few tens of degrees in the transport region. Comparison with magnetic oscillation phases determined directly from proximal pass data shows that electron density maxima occur ∼30°–50° earlier than azimuthal field maxima for both systems, ∼140°–160° earlier than colatitudinal field maxima for the northern system, nearer to antiphase than to leading quadrature, and ∼50°–70° later than colatitudinal field maxima for the southern system, somewhat less than lagging quadrature.
Dissolved Organic Matter Dynamics in the Epipelagic Northwest Pacific Low‐Latitude Western Boundary Current System: Insights From Optical Analyses
Authors: Wang Chao , Li Yizhen , Li Yan , Zhou Hui , Stubbins Aron , Dahlgren Randy A. , Wang Zhiheng , Guo Weidong
Published: August 2021

High‐resolution horizontal and vertical distribution of dissolved organic carbon (DOC), chromophoric, and fluorescent dissolved organic matter (CDOM and FDOM) were investigated in the western boundary current system of the tropical Northwest Pacific (<200 m) in autumn 2017. A strong correlation between DOC and stratification index indicated that the vertical DOC profile was primarily regulated by physical processes. The association of high aCDOM(254) with the maximum chlorophyll (Chl a) layer infers phytoplankton‐sourced dissolved organic matter (DOM). The aCDOM(325) and humic‐like FDOM (FDOMH) showed an accumulation in the deeper layer and positive correlations with apparent oxygen utilization and Chl a concentration at the maximum chlorophyll layer, suggesting that these components are related to microbial degradation of biogenic materials. Elevated Chl a at the frontal area between the North Equatorial Current (NEC) and cold Mindanao Eddy enhanced DOM production. Input waters from the NEC showed higher DOC, but lower FDOMH, than inflow waters from the New Guinea Coastal Current/Undercurrent (NGC(U)C). A mass balance model estimated a 6‐times higher lateral DOC flux from the NEC tropical‐gyre branch (12°N–7.5°N) than that from the subtropical‐gyre branch (12°N–17°N). Based on comparison with long‐term (1994–2015) average DOC fluxes for the same season, eddy and upstream processes contributed 38%, 46% and 40% of lateral DOC fluxes for the NEC tropical‐gyre branch, NGC(U)C and export North Equatorial Counter Current, respectively. These results demonstrated that the quasi‐permanent Mindanao and Halmahera eddies greatly enhance lateral export of DOM with altered properties throughout this large conjunction area.
Climate and Landscape Controls on the Water Balance in Temperate Forest Ecosystems: Testing Large Scale Controls on Undisturbed Catchments in the Central Appalachian Mountains of the US
Authors: Guillén Luis Andrés , Fernández Rodrigo , Gaertner Brandi , Zégre Nicolas Pierre
Published: August 2021

The long‐term water balance of catchments is given by precipitation partitioned into either runoff or evaporation. Understanding precipitation partitioning controls is a critical focus of hydrology and water resources management. A useful theoretical framework that serves their understanding is the Budyko Framework. Our purpose is to understand how Budyko's n parameter is related to different controls and what is its relevance to precipitation partitioning. We investigated the relative importance of the dryness index and the Budyko parameter for precipitation partitioning, then applied partial correlation analysis and multivariate regressions to find out which were the principal partitioning controls. We focused our research in the central Appalachian mountains located in the eastern United States, considered as water towers to metropolitan areas in the eastern and mid‐western US (e.g., Pittsburgh, Washington DC), and selected a set of catchments characterized by minimal human disturbance and with large proportions of temperate forests. We found that climate controls such as mean annual temperature and fraction of precipitation falling in the form of snow exert a higher influence on partitioning than landscape controls (e.g., forest cover, Normalized Difference Vegetation Index, and slope). Thus, the importance of vegetation as a primary driver of partitioning could not be confirmed based on regional or basin‐wide characteristics. On the other hand, the influence of topography, and elevation in particular, was highly ranked as important. Our study highlights that partitioning controls could differ between basins in the same climate region, especially in a complex, mountainous topography setting.
Using Complex Probability Amplitudes to Simulate Solute Transport in Composite Porous Media
Authors: Engdahl Nicholas B.
Published: August 2021

Probability amplitudes are fundamental to quantum mechanics and offer robust descriptions of complicated systems, which have allowed physicists to explain behaviors inaccessible to classical physics. This article ponders how some of the same conceptual underpinnings of the mathematics used for modeling quantum systems might be applied to subsurface water resources problems and speculates how these tools could facilitate applications on quantum computers. A probability amplitude‐based model for describing advective‐dispersive transport in porous media using linear operators is investigated. The proposed complex valued model decomposes spreading into two “sub‐continuum partial dispersion” coefficients, and this recovers classical spreading when the sum of these coefficients is the Fickian dispersion coefficient. However, the probability amplitudes have a many‐to‐one relationship to a probability distribution, so it embeds a level of heterogeneity into seemingly equivalent functions. Two propagators with different sub‐continuum coefficients may have the same macroscopic behavior when either is considered in isolation, but when they act on the other the system’s behavior changes. Differences in the amplitudes cause a reduction in spreading as velocity correlations are disrupted, despite both propagators having identical dispersion coefficients, and this cannot be achieved using classical methods without changing the dispersion coefficient. The main point is that these amplitude‐based models offer a way to embed information about the system into the propagators, instead of just “averaging it out” when making an upscaled model.
Electrochemical micro-aptasensors for exosome detection based on hybridization chain reaction amplification
Authors: Zhang Wenfen , Tian Zhenhua , Yang Shujie , Rich Joseph , Zhao Shuaiguo , Klingeborn Mikael , Huang Po-Hsun , Li Zhishang , Stout Alexander , Murphy Quinn , Patz Edward , Zhang Shusheng , Liu Guozhen , Huang Tony Jun
Published: August 2021

Exosomes are cell-derived nanovesicles that have recently gained popularity as potential biomarkers in liquid biopsies due to the large amounts of molecular cargo they carry, such as nucleic acids and proteins. However, most existing exosome-based analytical sensing methods struggle to achieve high sensitivity and high selectivity simultaneously. In this work, we present an electrochemical micro-aptasensor for the highly sensitive detection of exosomes by integrating a micropatterned electrochemical aptasensor and a hybridization chain reaction (HCR) signal amplification method. Specifically, exosomes are enriched on CD63 aptamer-functionalized electrodes and then recognized by HCR products with avidin-horseradish peroxidase (HRP) attached using EpCAM aptamers as bridges. Subsequently, the current signal that is generated through the enzyme reaction between the HRP enzyme and 3,3’,5,5’-tetramethylbenzidine (TMB)/H2O2 directly correlates to the amount of bound HRP on the HCR products and thus to the number of target exosomes. By introducing anti-EpCAM aptamers, micro-aptasensors can detect cancerous exosomes with high specificity. Due to the micropatterned electrodes and HCR dual-amplification strategy, the micro-aptasensors achieve a linear detection response for a wide range of exosome concentrations from 2.5×103 to 1×107 exosomes/mL, with a detection limit of 5×102 exosomes/mL. Moreover, our method successfully detects lung cancer exosomes in serum samples of early-stage and late-stage lung cancer patients, showcasing the great potential for early cancer diagnosis.
Measuring expression heterogeneity of single-cell cytoskeletal protein complexes
Authors: Vlassakis Julea , Hansen Louise L. , Higuchi-Sanabria Ryo , Zhou Yun , Tsui C. Kimberly , Dillin Andrew , Huang Haiyan , Herr Amy E.
Published: August 2021

Multimeric cytoskeletal protein complexes orchestrate normal cellular function. However, protein-complex distributions in stressed, heterogeneous cell populations remain unknown. Cell staining and proximity-based methods have limited selectivity and/or sensitivity for endogenous multimeric protein-complex quantification from single cells. We introduce micro-arrayed, differential detergent fractionation to simultaneously detect protein complexes in hundreds of individual cells. Fractionation occurs by 60 s size-exclusion electrophoresis with protein complex-stabilizing buffer that minimizes depolymerization. Proteins are measured with a ~5-hour immunoassay. Co-detection of cytoskeletal protein complexes in U2OS cells treated with filamentous actin (F-actin) destabilizing Latrunculin A detects a unique subpopulation (~2%) exhibiting downregulated F-actin, but upregulated microtubules. Thus, some cells may upregulate other cytoskeletal complexes to counteract the stress of Latrunculin A treatment. We also sought to understand the effect of non-chemical stress on cellular heterogeneity of F-actin. We find heat shock may dysregulate filamentous and globular actin correlation. In this work, our assay overcomes selectivity limitations to biochemically quantify single-cell protein complexes perturbed with diverse stimuli.
Live cell tagging tracking and isolation for spatial transcriptomics using photoactivatable cell dyes
Authors: Genshaft Alex S , Ziegler Carly G. K. , Tzouanas Constantine N. , Mead Benjamin E. , Jaeger Alex M. , Navia Andrew W. , King Ryan P. , Mana Miyeko D. , Huang Siyi , Mitsialis Vanessa , Snapper Scott B. , Yilmaz Ömer H. , Jacks Tyler , Van Humbeck Jeffrey F. , Shalek Alex K.
Published: August 2021

A cell’s phenotype and function are influenced by dynamic interactions with its microenvironment. To examine cellular spatiotemporal activity, we developed SPACECAT—Spatially PhotoActivatable Color Encoded Cell Address Tags—to annotate, track, and isolate cells while preserving viability. In SPACECAT, samples are stained with photocaged fluorescent molecules, and cells are labeled by uncaging those molecules with user-patterned near-UV light. SPACECAT offers single-cell precision and temporal stability across diverse cell and tissue types. Illustratively, we target crypt-like regions in patient-derived intestinal organoids to enrich for stem-like and actively mitotic cells, matching literature expectations. Moreover, we apply SPACECAT to ex vivo tissue sections from four healthy organs and an autochthonous lung tumor model. Lastly, we provide a computational framework to identify spatially-biased transcriptome patterns and enriched phenotypes. This minimally perturbative and broadly applicable method links cellular spatiotemporal and/or behavioral phenotypes with diverse downstream assays, enabling insights into the connections between tissue microenvironments and (dys)function.
TMEM16F and dynamins control expansive plasma membrane reservoirs
Authors: Deisl Christine , Hilgemann Donald W. , Syeda Ruhma , Fine Michael
Published: August 2021

Cells can expand their plasma membrane laterally by unfolding membrane undulations and by exocytosis. Here, we describe a third mechanism involving invaginations held shut by the membrane adapter, dynamin. Compartments open when Ca activates the lipid scramblase, TMEM16F, anionic phospholipids escape from the cytoplasmic monolayer in exchange for neutral lipids, and dynamins relax. Deletion of TMEM16F or dynamins blocks expansion, with loss of dynamin expression generating a maximally expanded basal plasma membrane state. Re-expression of dynamin2 or its GTPase-inactivated mutant, but not a lipid binding mutant, regenerates reserve compartments and rescues expansion. Dynamin2-GFP fusion proteins form punctae that rapidly dissipate from these compartments during TMEM16F activation. Newly exposed compartments extend deeply into the cytoplasm, lack numerous organellar markers, and remain closure-competent for many seconds. Without Ca, compartments open slowly when dynamins are sequestered by cytoplasmic dynamin antibodies or when scrambling is mimicked by neutralizing anionic phospholipids and supplementing neutral lipids. Activation of Ca-permeable mechanosensitive channels via cell swelling or channel agonists opens the compartments in parallel with phospholipid scrambling. Thus, dynamins and TMEM16F control large plasma membrane reserves that open in response to lateral membrane stress and Ca influx.
A unified model of human hemoglobin switching through single-cell genome editing
Authors: Shen Yong , Verboon Jeffrey M. , Zhang Yuannyu , Liu Nan , Kim Yoon Jung , Marglous Samantha , Nandakumar Satish K. , Voit Richard A. , Fiorini Claudia , Ejaz Ayesha , Basak Anindita , Orkin Stuart H. , Xu Jian , Sankaran Vijay G.
Published: August 2021

Key mechanisms of fetal hemoglobin (HbF) regulation and switching have been elucidated through studies of human genetic variation, including mutations in the HBG1/2 promoters, deletions in the β-globin locus, and variation impacting BCL11A. While this has led to substantial insights, there has not been a unified understanding of how these distinct genetically-nominated elements, as well as other key transcription factors such as ZBTB7A, collectively interact to regulate HbF. A key limitation has been the inability to model specific genetic changes in primary isogenic human hematopoietic cells to uncover how each of these act individually and in aggregate. Here, we describe a single-cell genome editing functional assay that enables specific mutations to be recapitulated individually and in combination, providing insights into how multiple mutation-harboring functional elements collectively contribute to HbF expression. In conjunction with quantitative modeling and chromatin capture analyses, we illustrate how these genetic findings enable a comprehensive understanding of how distinct regulatory mechanisms can synergistically modulate HbF expression.
Male sperm storage impairs sperm quality in the zebrafish
Authors: Cattelan Silvia , Gasparini Clelia
Published: August 2021

Variation in sperm traits is widely documented both at inter- and intraspecific level. However, sperm traits vary also between ejaculates of the same male, due for example, to fluctuations in female availability. Variability in the opportunities to mate can indeed have important consequences for sperm traits, as it determines how often sperm are used, and thus the rate at which they are produced and how long they are stored before the mating. While being stored within males’ bodies, sperm are subjected to ageing due to oxidative stress. Sperm storage may significantly impair sperm quality, but evidence linking male sperm storage and variation in sperm traits is still scarce. Here, we tested the effect of the duration of sperm storage on within-male variation in sperm traits in the zebrafish, Danio rerio. We found that without mating opportunities, sperm number increased as storage duration increased, indicating that sperm continue to be produced and accumulate over time within males without being discharged in another way. Long sperm storage (12 days) was associated with an overall impairment in sperm quality, namely sperm motility, sperm longevity, and sperm DNA fragmentation, indicating that sperm aged, and their quality declined during storage. Our results confirm that male sperm storage may generate substantial variation in sperm phenotype, a source of variation which is usually neglected but that should be accounted for in experimental protocols aiming to assay sperm traits or maximise fertilization success.
Dipeptidyl peptidase-4 inhibitor cardiovascular safety in patients with type 2 diabetes, with cardiovascular and renal disease: a retrospective cohort study
Authors: Baksh Sheriza , Wen Jiajun , Mansour Omar , Chang Hsien-Yen , McAdams-DeMarco Mara , Segal Jodi B. , Ehrhardt Stephan , Alexander G. Caleb
Published: August 2021

Clinical trials investigating cardiovascular safety of dipeptidyl peptidase-IV inhibitors (DPP-4i) among patients with cardiovascular and renal disease rarely recruit patients with renal impairment, despite associations with increased risk for major adverse cardiovascular events (MACE). We investigated the risk of MACE associated with the use of DPP-4i among these high-risk patients. Using a new-user, retrospective, cohort design, we analyzed 2010–2015 IBM MarketScan Commercial Claims and Encounters for patients with diabetes, comorbid with cardiovascular disease and/or renal impairment. We compared time to first MACE for DPP-4i versus sulfonylurea and versus metformin. Of 113,296 individuals, 9146 (8.07%) were new DPP-4i users, 17,481 (15.43%) were new sulfonylurea users, and 88,596 (78.20%) were new metformin users. Exposure groups were not mutually exclusive. DPP-4i was associated with lower risk for MACE than sulfonylurea (aHR 0.84; 95% CI 0.74, 0.93) and similar risk for MACE to metformin (aHR 1.07; 95% CI [1.04, 1.16]). DPP-4i use was associated with lower risk for MACE compared to sulfonylureas and similar risk for MACE compared to metformin. This association was most evident in the first year of therapy, suggesting that DPP-4i is a safer choice than sulfonylurea for diabetes treatment initiation in high-risk patients.
Free fatty acids, glicentin and glucose-dependent insulinotropic polypeptide as potential major determinants of fasting substrate oxidation
Authors: Hummel Julia , Fritsche Louise , Vosseler Andreas , Dannecker Corinna , Hoene Miriam , Kantartzis Konstantinos , Häring Hans-Ulrich , Stefan Norbert , Machann Jürgen , Birkenfeld Andreas L. , Weigert Cora , Wagner Robert , Peter Andreas , Fritsche Andreas , Heni Martin
Published: August 2021

The selection of carbohydrates or fat to generate intracellular energy is thought to be crucial for long-term metabolic health. While most studies assess fuel selection after a metabolic challenge, the determinants of substrate oxidation in the fasted state remain largely unexplored. We therefore assessed the respiratory quotient by indirect calorimetry as a read-out for substrate oxidation following an overnight fast. This cross-sectional analysis consisted of 192 (92 women, 100 men) either lean or obese participants. Following an overnight fast, the respiratory quotient (RQ) was assessed, after which a 5-point 75-g oral glucose tolerance test was performed. Unlike glucose and insulin, fasting free fatty acids (FFA) correlated negatively with fasting RQ (p < 0.0001). Participants with high levels of the ketone body β-hydroxybutyric acid had significantly lower RQ values. Fasting levels of glucose-dependent insulinotropic polypeptide (GIP) and glicentin were positively associated with fasting RQ (allp ≤ 0.03), whereas GLP-1 showed no significant association. Neither BMI, nor total body fat, nor body fat distribution correlated with fasting RQ. No relationship between the RQ and diabetes or the metabolic syndrome could be observed. In the fasting state, FFA concentrations were strongly linked to the preferentially oxidized substrate. Our data did not indicate any relationship between fasting substrate oxidation and metabolic diseases, including obesity, diabetes, and the metabolic syndrome. Since glicentin and GIP are linked to fuel selection in the fasting state, novel therapeutic approaches that target these hormones may have the potential to modulate substrate oxidation.
Comparison between intervertebral oblique lumbar interbody fusion and transforaminal lumbar interbody fusion: a multicenter study
Authors: Takaoka Hiromitsu , Inage Kazuhide , Eguchi Yawara , Shiga Yasuhiro , Furuya Takeo , Maki Satoshi , Aoki Yasuchika , Inoue Masahiro , Fujiyoshi Takayuki , Miyamoto Takuya , Noguchi Yuji , Nakamura Shinichiro , Kinoshita Tomoaki , Kamada Takahito , Takahashi Hiroshi , Saito Junya , Norimoto Masaki , Kotani Toshiaki , Sakuma Tsuyoshi , Iijima Yasushi , Ishikawa Tetsuhiro , Umimura Tomotaka , Ohta Mitsutoshi , Suzuki-Narita Miyako , Enomoto Keigo , Sato Takashi , Sato Masashi , Suzuki Masahiro , Hozumi Takashi , Kim Geundong , Mizuki Norichika , Tsuchiya Ryuto , Otagiri Takuma , Mukaihata Tomohito , Hishiya Takahisa , Ohtori Seiji , Orita Sumihisa
Published: August 2021

This study aimed to perform a comparative analysis of postoperative results between lumbar degenerative spondylolisthesis (LDS) treated with oblique lateral interbody fusion (OLIF) and transforaminal lumbar interbody fusion (TLIF) from the Chiba spine surgery registry database. Sixty-five patients who underwent single-level OLIF (O group) for LDS with ≥ 3 years’ follow-up were retrospectively reviewed. The control group comprised 78 patients who underwent single-level TLIF (T group). The analyzed variables included global alignment, radiological parameters of fused segments, asymptomatic and symptomatic ASD incidence, clinical outcomes at 3 years postoperatively using the Japanese Orthopedic Association Back Pain Evaluation Questionnaire data, visual analogue scale scores for low back pain, lower extremity pain, and lower extremity numbness. There was no significant change in global alignment between the two groups. The rate of improvement in anterior intervertebral disc height was not significantly different between the groups at 1-month postoperatively. However, at the final evaluation, the anterior intervertebral disc height and incidence of asymptomatic ASD were significantly higher in the O group. There was no significant difference in symptomatic ASD, reoperation cases, or clinical results between groups. Thus, single-level OLIF can maintain the corrected disc height, but as it has no effect on global alignment, its benefit is limited.
Cartilage oligomeric matrix protein as a marker of progressive liver fibrosis in biliary atresia
Authors: Udomsinprasert Wanvisa , Angkathunyakul Napat , Jittikoon Jiraphun , Chaikledkaew Usa , Vejchapipat Paisarn , Poovorawan Yong , Honsawek Sittisak
Published: August 2021

This study aimed to determine whether mRNA and protein levels of cartilage oligomeric matrix protein (COMP), a glycoprotein responsible for modulating homeostasis of extracellular matrix, in the systemic and local liver environments were associated with clinical parameters of biliary atresia (BA) patients and might serve as a biomarker for BA severity. COMP protein levels in the circulation of 96 BA patients and 56 healthy controls and its mRNA and protein expressions in the liver of 20 BA patients and 5 non-BA patients were evaluated using enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and immunohistochemistry, respectively. In the circulation of BA patients, COMP levels were significantly higher than those in healthy controls. Compared with early-stage BA patients, those with advanced-stage including jaundice, fibrosis, and hepatic dysfunction had significantly increased circulating COMP levels. Raised circulating COMP levels were found to be independently correlated with degree of liver fibrosis. Survival analysis showed that elevated circulating COMP levels were significantly associated with decreased survival of BA patients. Receiver-operating characteristic curve analysis unveiled a diagnostic value of circulating COMP as a non-invasive biomarker of BA (AUC = 0.99), with a sensitivity of 100.0% and a specificity of 98.2%. In the liver, both COMP mRNA and protein expressions of BA patients with fibrosis were significantly greater than those of BA patients without fibrosis and non-BA patients. Collectively, increased circulating COMP might reflect unfavorable outcome of BA patients and have potential as a novel biomarker for the disease severity following Kasai-operation.
A study of ladder-like silk foothold for the locomotion of bagworms
Authors: Yoshioka Taiyo , Yukuhiro Fumiko , Kameda Tsunenori
Published: August 2021

While walking on horizontal substrates, caterpillars skilfully engage all their legs, including three pairs of thoracic legs and a maximum of five pairs of prolegs, to move in a flexible wave-like motion. Such locomotory behaviours, represented by ‘crawling’ and ‘inching’ motions, have widely inspired the development of locomotion systems in soft robotics. However, bagworms are unable to use their prolegs for walking because these are always accommodated in a portable bag; thus, they are unable to walk using such general locomotory behaviours. Indeed, how they walk with only three pairs of thoracic legs is unknown at present. In this study, we show that bagworms construct a ladder-like foothold using their silk to walk without using prolegs. This enables them to walk not only on horizontal floor surfaces but also on wall and ceiling surfaces, even those with slippery or smooth surfaces. They construct the foothold by spinning a continuous silk thread in a zigzag manner and controlling the discharge of adhesive to attach the folded parts of the silk to a substrate. Discovery of this elaborate silk utilisation technique offers fresh insights into the diversity of silk use in lepidopteran larvae and provides potential designs for robot locomotion systems.
Continuous subcutaneous insulin infusion alters microRNA expression and glycaemic variability in children with type 1 diabetes
Authors: Scott Emma S. , Januszewski Andrzej S. , Carroll Luke M. , Fulcher Gregory R. , Joglekar Mugdha V. , Hardikar Anandwardhan A. , Jones Timothy W. , Davis Elizabeth A. , Jenkins Alicia J.
Published: August 2021

To determine whether continuous subcutaneous insulin infusion (CSII) vs. multiple daily injections (MDI) therapy from near-diagnosis of type 1 diabetes is associated with reduced glycaemic variability (GV) and altered microRNA (miRNAs) expression. Adolescents (74% male) within 3-months of diabetes diagnosis (n = 27) were randomized to CSII (n = 12) or MDI. HbA1c, 1-5-Anhydroglucitol (1,5-AG), high sensitivity C-peptide and a custom TaqMan qPCR panel of 52 miRNAs were measured at baseline and follow-up (median (LQ-UQ); 535 (519–563) days). There were no significant differences between groups in baseline or follow-up HbA1c or C-peptide, nor baseline miRNAs. Mean ± SD 1,5-AG improved with CSII vs. MDI (3.1 ± 4.1 vs. − 2.2 ± − 7.0 mg/ml respectively, P = 0.029). On follow-up 11 miRNAs associated with diabetes vascular complications had altered expression in CSII-users. Early CSII vs. MDI use is associated with lower GV and less adverse vascular-related miRNAs. Relationships with future complications are of interest.
A genome-wide association study of quantitative computed tomographic emphysema in Korean populations
Authors: Sin Sooim , Choi Hye-Mi , Lim Jiwon , Kim Jeeyoung , Bak So Hyeon , Choi Sun Shim , Park Jinkyeong , Lee Jin Hwa , Oh Yeon-Mok , Lee Mi Kyeong , Hobbs Brian D. , Cho Michael H. , Silverman Edwin K. , Kim Woo Jin
Published: August 2021

Emphysema is an important feature of chronic obstructive pulmonary disease (COPD). Genetic factors likely affect emphysema pathogenesis, but this question has predominantly been studied in those of European ancestry. In this study, we sought to determine genetic components of emphysema severity and characterize the potential function of the associated loci in Korean population. We performed a genome-wide association study (GWAS) on quantitative emphysema in subjects with or without COPD from two Korean COPD cohorts. We investigated the functional consequences of the loci using epigenetic annotation and gene expression data. We also compared our GWAS results with an epigenome-wide association study and previous differential gene expression analysis. In total, 548 subjects (476 [86.9%] male) including 514 COPD patients were evaluated. We identified one genome-wide significant SNP (P < 5.0 × 10–8), rs117084279, near PIBF1. We identified an additional 57 SNPs (P < 5.0 × 10–6) associated with emphysema in all subjects, and 106 SNPs (P < 5.0 × 10–6) in COPD patients. Of these candidate SNPs, 2 (rs12459249, rs11667314) near CYP2A6 were expression quantitative trait loci in lung tissue and a SNP (rs11214944) near NNMT was an expression quantitative trait locus in whole blood. Of note, rs11214944 was in linkage disequilibrium with variants in enhancer histone marks in lung tissue. Several genes near additional SNPs were identified in our previous EWAS study with nominal level of significance. We identified a novel SNP associated with quantitative emphysema on CT. Including the novel SNP, several candidate SNPs in our study may provide clues to the genetic etiology of emphysema in Asian populations. Further research and validation of the loci will help determine the genetic factors for the development of emphysema.
The ABCC4 gene is associated with pyometra in golden retriever dogs
Authors: Arendt Maja , Ambrosen Aime , Fall Tove , Kierczak Marcin , Tengvall Katarina , Meadows Jennifer R. S. , Karlsson Åsa , Lagerstedt Anne-Sofie , Bergström Tomas , Andersson Göran , Lindblad-Toh Kerstin , Hagman Ragnvi
Published: August 2021

Pyometra is one of the most common diseases in female dogs, presenting as purulent inflammation and bacterial infection of the uterus. On average 20% of intact female dogs are affected before 10 years of age, a proportion that varies greatly between breeds (3–66%). The clear breed predisposition suggests that genetic risk factors are involved in disease development. To identify genetic risk factors associated with the disease, we performed a genome-wide association study (GWAS) in golden retrievers, a breed with increased risk of developing pyometra (risk ratio: 3.3). We applied a mixed model approach comparing 98 cases, and 96 healthy controls and identified an associated locus on chromosome 22 (p = 1.2 × 10–6, passing Bonferroni corrected significance). This locus contained five significantly associated SNPs positioned within introns of the ATP-binding cassette transporter 4 (ABCC4) gene. This gene encodes a transmembrane transporter that is important for prostaglandin transport. Next generation sequencing and genotyping of cases and controls subsequently identified four missense SNPs within the ABCC4 gene. One missense SNP at chr22:45,893,198 (p.Met787Val) showed complete linkage disequilibrium with the associated GWAS SNPs suggesting a potential role in disease development. Another locus on chromosome 18 overlapping the TESMIN gene, is also potentially implicated in the development of the disease.
Single cell morphology distinguishes genotype and drug effect in Hereditary Spastic Paraplegia
Authors: Wali Gautam , Berkovsky Shlomo , Whiten Daniel R. , Mackay-Sim Alan , Sue Carolyn M.
Published: August 2021

A central need for neurodegenerative diseases is to find curative drugs for the many clinical subtypes, the causative gene for most cases being unknown. This requires the classification of disease cases at the genetic and cellular level, an understanding of disease aetiology in the subtypes and the development of phenotypic assays for high throughput screening of large compound libraries. Herein we describe a method that facilitates these requirements based on cell morphology that is being increasingly used as a readout defining cell state. In patient-derived fibroblasts we quantified 124 morphological features in 100,000 cells from 15 people with two genotypes (SPAST and SPG7) of Hereditary Spastic Paraplegia (HSP) and matched controls. Using machine learning analysis, we distinguished between each genotype and separated them from controls. Cell morphologies changed with treatment with noscapine, a tubulin-binding drug, in a genotype-dependent manner, revealing a novel effect on one of the genotypes (SPG7). These findings demonstrate a method for morphological profiling in fibroblasts, an accessible non-neural cell, to classify and distinguish between clinical subtypes of neurodegenerative diseases, for drug discovery, and potentially for biomarkers of disease severity and progression.
Towards a better understanding of the posttreatment hemodynamic behaviors in femoropopliteal arteries through personalized computational models based on OCT images
Authors: Gökgöl Can , Ueki Yasushi , Abler Daniel , Diehm Nicolas , Engelberger Rolf P. , Otsuka Tatsuhiko , Räber Lorenz , Büchler Philippe
Published: August 2021

The hemodynamic behavior following endovascular treatment of patients with peripheral arterial disease plays a significant role on the occurrence of restenosis in femoro-popliteal (FP) arteries. The atheroprone flow conditions that are generally accepted to promote restenosis can be calculated by computational fluid dynamics (CFD) analyses, and these results can be used to assess individualized treatment outcomes. However, the impact of endovascular therapy on the flow behaviors of FP arteries are still poorly understood, as the imaging modalities used in existing numerical works (X-ray angiography, computed tomography angiography) are unable to accurately represent the post-treatment arterial geometry due to their low resolutions. Therefore, this study proposes a new algorithm that combines intra-arterial lumen geometry obtained from high-resolution optical coherence tomography (OCT) images with centerlines generated from X-ray images to reconstruct the FP artery with an in-plane resolution of 10 µm. This superior accuracy allows modeling characteristic geometrical structures, such as angioplasty-induced arterial dissections, that are too small to be reconstructed with other imaging modalities. The framework is applied on the clinical data of patients treated either with only-percutaneous transluminal angioplasty (PTA) (n = 4) or PTA followed by stenting (n = 4). Based on the generated models, PTA was found to cause numerous arterial dissections, covering approximately 10% of the total surface area of the lumen, whereas no dissections were identified in the stented arteries. CFD simulations were performed to investigate the hemodynamic conditions before and after treatment. Regardless of the treatment method, the areas affected by low time-averaged wall shear stress (< 0.5 Pa) were significantly higher (p < 0.05) following endovascular therapy (pre-PTA: 0.95 ± 0.59 cm2; post-PTA: 2.10 ± 1.09cm2; post-stent: 3.10 ± 0.98 cm2). There were no statistical differences between the PTA and the stent groups. However, within the PTA group, adverse hemodynamics were mainly concentrated at regions created by arterial dissections, which may negatively impact the outcomes of a leave-nothing-behind strategy. These observations show that OCT-based numerical models have great potential to guide clinicians regarding the optimal treatment approach.
The Upper Triassic Polzberg palaeobiota from a marine Konservat-Lagerstätte deposited during the Carnian Pluvial Episode in Austria
Authors: Lukeneder Alexander , Lukeneder Petra
Published: August 2021

A rich assemblage of various marine taxa from the lower Carnian Polzberg Konservat-Lagerstätte near Lunz am See (Northern Calcareous Alps, Lower Austria) is described for the first time in detail. The fossiliferous layers were deposited during the Julian 2 Ib (Austrotrachyceras austriacum Zone, Austrotrachyceras minor biohorizon). The fine-laminated Reingraben Shales comprise abundant and well-preserved members of the marine Carnian food chain. Invertebrates with the bivalve Halobia, the ammonite Austrotrachyceras and the coleoid Phragmoteuthis dominate over vertebrate actinopterygian fishes. Fragile groups such as polychaetes and isopods are entirely preserved as soft body fossils. The diverse assemblage comprises ammonites (Austrotrachyceras, Carnites, Sageceras, Simonyceras), coleoids (Phragmoteuthis, Lunzoteuthis), bivalves (Halobia), gastropods (caenogastropods/heterobranchs), one echinoid, thylacocephalan arthropods (Austriocaris), crustaceans (the decapod Platychela and isopods such as Obtusotelson, Discosalaputium), polychaetes (Palaeoaphrodite sp., eunicid polychaete), acytinopterygians (Saurichthys, Polzbergia, Peltopleurus, Habroichthys), cartilaginous fishes (Acrodus), coelacanth fish (“Coelacanthus”), a lungfish (Tellerodus), and a conodont cluster (Mosherella). Regurgitalites produced by large durophagous fish and coprolites produced by piscivorous actinopterygians accompany the Polzberg palaeobiota along with rare plant remains (Voltzia). The entire fauna of Polzberg and the excellent preservation of the specimens present a window into the Upper Triassic assemblage and palaeoenvironment during the so-called Carnian Pluvial Episode (CPE) in the early Mesozoic. The occurrence of the freshwater lungfish Tellerodus and the branchiopod Eustheria, a member of brackish to freshwater environments, points to the influence of occasional freshwater pulses or sediment transport events on the marine environment. The Polzberg palaeobiota was deposited during the global CPE, triggering the environmental conditions of the Polzberg Basin and resulting in the formation of the Reingraben Shales with the Polzberg Konservat-Lagerstätte.
Evaluation of focus and deep learning methods for automated image grading and factors influencing image quality in adaptive optics ophthalmoscopy
Authors: Sampson Danuta M. , Alonso-Caneiro David , Chew Avenell L. , La Jonathan , Roshandel Danial , Wang Yufei , Khan Jane C. , Chelva Enid , Stevenson Paul G. , Chen Fred K.
Published: August 2021

Adaptive optics flood illumination ophthalmoscopy (AO-FIO) is an established imaging tool in the investigation of retinal diseases. However, the clinical interpretation of AO-FIO images can be challenging due to varied image quality. Therefore, image quality assessment is essential before interpretation. An image assessment tool will also assist further work on improving the image quality, either during acquisition or post processing. In this paper, we describe, validate and compare two automated image quality assessment methods; the energy of Laplacian focus operator (LAPE; not commonly used but easily implemented) and convolutional neural network (CNN; effective but more complex approach). We also evaluate the effects of subject age, axial length, refractive error, fixation stability, disease status and retinal location on AO-FIO image quality. Based on analysis of 10,250 images of 50 × 50 μm size, at 41 retinal locations, from 50 subjects we demonstrate that CNN slightly outperforms LAPE in image quality assessment. CNN achieves accuracy of 89%, whereas LAPE metric achieves 73% and 80% (for a linear regression and random forest multiclass classifier methods, respectively) compared to ground truth. Furthermore, the retinal location, age and disease are factors that can influence the likelihood of poor image quality.
Inhibiting SARS-CoV-2 infection in vitro by suppressing its receptor, angiotensin-converting enzyme 2, via aryl-hydrocarbon receptor signal
Authors: Tanimoto Keiji , Hirota Kiichi , Fukazawa Takahiro , Matsuo Yoshiyuki , Nomura Toshihito , Tanuza Nazmul , Hirohashi Nobuyuki , Bono Hidemasa , Sakaguchi Takemasa
Published: August 2021

Since understanding molecular mechanisms of SARS-CoV-2 infection is extremely important for developing effective therapies against COVID-19, we focused on the internalization mechanism of SARS-CoV-2 via ACE2. Although cigarette smoke is generally believed to be harmful to the pathogenesis of COVID-19, cigarette smoke extract (CSE) treatments were surprisingly found to suppress the expression of ACE2 in HepG2 cells. We thus tried to clarify the mechanism of CSE effects on expression of ACE2 in mammalian cells. Because RNA-seq analysis suggested that suppressive effects on ACE2 might be inversely correlated with induction of the genes regulated by aryl hydrocarbon receptor (AHR), the AHR agonists 6-formylindolo(3,2-b)carbazole (FICZ) and omeprazole (OMP) were tested to assess whether those treatments affected ACE2 expression. Both FICZ and OMP clearly suppressed ACE2 expression in a dose-dependent manner along with inducing CYP1A1. Knock-down experiments indicated a reduction of ACE2 by FICZ treatment in an AHR-dependent manner. Finally, treatments of AHR agonists inhibited SARS-CoV-2 infection into Vero E6 cells as determined with immunoblotting analyses detecting SARS-CoV-2 specific nucleocapsid protein. We here demonstrate that treatment with AHR agonists, including FICZ, and OMP, decreases expression of ACE2 via AHR activation, resulting in suppression of SARS-CoV-2 infection in mammalian cells.
SFPQ rescues F508del-CFTR expression and function in cystic fibrosis bronchial epithelial cells
Authors: Kumar Parameet , Soni Dharmendra Kumar , Sen Chaitali , Larsen Mads B. , Mazan-Mamczarz Krystyna , Piao Yulan , De Supriyo , Gorospe Myriam , Frizzell Raymond A. , Biswas Roopa
Published: August 2021

Cystic fibrosis (CF) occurs as a result of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which lead to misfolding, trafficking defects, and impaired function of the CFTR protein. Splicing factor proline/glutamine-rich (SFPQ) is a multifunctional nuclear RNA-binding protein (RBP) implicated in the regulation of gene expression pathways and intracellular trafficking. Here, we investigated the role of SFPQ in the regulation of the expression and function of F508del-CFTR in CF lung epithelial cells. We find that the expression of SFPQ is reduced in F508del-CFTR CF epithelial cells compared to WT-CFTR control cells. Interestingly, the overexpression of SFPQ in CF cells increases the expression as well as rescues the function of F508del-CFTR. Further, comprehensive transcriptome analyses indicate that SFPQ plays a key role in activating the mutant F508del-CFTR by modulating several cellular signaling pathways. This is the first report on the role of SFPQ in the regulation of expression and function of F508del-CFTR in CF lung disease. Our findings provide new insights into SFPQ-mediated molecular mechanisms and point to possible novel epigenetic therapeutic targets for CF and related pulmonary diseases.