bluuebunny/crossref_metadata_2025 huggingface dataset:
Homotypic clustering of L1 and B1/Alu repeats compartmentalizes the 3D genome
Authors: Lu J. Yuyang , Chang Lei , Li Tong , Wang Ting , Yin Yafei , Zhan Ge , Han Xue , Zhang Ke , Tao Yibing , Percharde Michelle , Wang Liang , Peng Qi , Yan Pixi , Zhang Hui , Bi Xianju , Shao Wen , Hong Yantao , Wu Zhongyang , Ma Runze , Wang Peizhe , Li Wenzhi , Zhang Jing , Chang Zai , Hou Yingping , Zhu Bing , Ramalho-Santos Miguel , Li Pilong , Xie Wei , Na Jie , Sun Yujie , Shen Xiaohua
Published: January 2021

Organization of the genome into euchromatin and heterochromatin appears to be evolutionarily conserved and relatively stable during lineage differentiation. In an effort to unravel the basic principle underlying genome folding, here we focus on the genome itself and report a fundamental role for L1 (LINE1 or LINE-1) and B1/Alu retrotransposons, the most abundant subclasses of repetitive sequences, in chromatin compartmentalization. We find that homotypic clustering of L1 and B1/Alu demarcates the genome into grossly exclusive domains, and characterizes and predicts Hi-C compartments. Spatial segregation of L1-rich sequences in the nuclear and nucleolar peripheries and B1/Alu-rich sequences in the nuclear interior is conserved in mouse and human cells and occurs dynamically during the cell cycle. In addition, de novo establishment of L1 and B1 nuclear segregation is coincident with the formation of higher-order chromatin structures during early embryogenesis and appears to be critically regulated by L1 and B1 transcripts. Importantly, depletion of L1 transcripts in embryonic stem cells drastically weakens homotypic repeat contacts and compartmental strength, and disrupts the nuclear segregation of L1- or B1-rich chromosomal sequences at genome-wide and individual sites. Mechanistically, nuclear co-localization and liquid droplet formation of L1 repeat DNA and RNA with heterochromatin protein HP1α suggest a phase-separation mechanism by which L1 promotes heterochromatin compartmentalization. Taken together, we propose a genetically encoded model in which L1 and B1/Alu repeats blueprint chromatin macrostructure. Our model explains the robustness of genome folding into a common conserved core, on which dynamic gene regulation is overlaid across cells.
Gate-tunable photodetector and ambipolar transistor implemented using a graphene/MoSe2 barristor
Authors: Oh Gwangtaek , Jeon Ji Hoon , Kim Young Chul , Ahn Yeong Hwan , Park Bae Ho
Published: January 2021

Next-generation electronic and optoelectronic devices require a high-quality channel layer. Graphene is a good candidate because of its high carrier mobility and unique ambipolar transport characteristics. However, the on/off ratio and photoresponsivity of graphene are typically low. Transition metal dichalcogenides (e.g., MoSe2) are semiconductors with high photoresponsivity but lower mobility than that of graphene. Here, we propose a graphene/MoSe2 barristor with a high-k ion-gel gate dielectric. It shows a high on/off ratio (3.3 × 104) and ambipolar behavior that is controlled by an external bias. The barristor exhibits very high external quantum efficiency (EQE, 66.3%) and photoresponsivity (285.0 mA/W). We demonstrate that an electric field applied to the gate electrode substantially modulates the photocurrent of the barristor, resulting in a high gate tuning ratio (1.50 μA/V). Therefore, this barristor shows potential for use as an ambipolar transistor with a high on/off ratio and a gate-tunable photodetector with a high EQE and responsivity.
Integrated neuromorphic computing networks by artificial spin synapses and spin neurons
Authors: Yang Seungmo , Shin Jeonghun , Kim Taeyoon , Moon Kyoung-Woong , Kim Jaewook , Jang Gabriel , Hyeon Da Seul , Yang Jungyup , Hwang Chanyong , Jeong YeonJoo , Hong Jin Pyo
Published: January 2021

One long-standing goal in the emerging neuromorphic field is to create a reliable neural network hardware implementation that has low energy consumption, while providing massively parallel computation. Although diverse oxide-based devices have made significant progress as artificial synaptic and neuronal components, these devices still need further optimization regarding linearity, symmetry, and stability. Here, we present a proof-of-concept experiment for integrated neuromorphic computing networks by utilizing spintronics-based synapse (spin-S) and neuron (spin-N) devices, along with linear and symmetric weight responses for spin-S using a stripe domain and activation functions for spin-N. An integrated neural network of electrically connected spin-S and spin-N successfully proves the integration function for a simple pattern classification task. We simulate a spin-N network using the extracted device characteristics and demonstrate a high classification accuracy (over 93%) for the spin-S and spin-N optimization without the assistance of additional software or circuits required in previous reports. These experimental studies provide a new path toward establishing more compact and efficient neural network systems with optimized multifunctional spintronic devices.
Enhanced piezoelectricity from highly polarizable oriented amorphous fractions in biaxially oriented poly(vinylidene fluoride) with pure β crystals
Authors: Huang Yanfei , Rui Guanchun , Li Qiong , Allahyarov Elshad , Li Ruipeng , Fukuto Masafumi , Zhong Gan-Ji , Xu Jia-Zhuang , Li Zhong-Ming , Taylor Philip L. , Zhu Lei
Published: January 2021

Piezoelectric polymers hold great potential for various electromechanical applications, but only show low performance, with |d33 | < 30 pC/N. We prepare a highly piezoelectric polymer (d33 = −62 pC/N) based on a biaxially oriented poly(vinylidene fluoride) (BOPVDF, crystallinity = 0.52). After unidirectional poling, macroscopically aligned samples with pure β crystals are achieved, which show a high spontaneous polarization (Ps) of 140 mC/m2. Given the theoretical limit of Ps,β = 188 mC/m2 for the neat β crystal, the high Ps cannot be explained by the crystalline-amorphous two-phase model (i.e., Ps,β = 270 mC/m2). Instead, we deduce that a significant amount (at least 0.25) of an oriented amorphous fraction (OAF) must be present between these two phases. Experimental data suggest that the mobile OAF resulted in the negative and high d33 for the poled BOPVDF. The plausibility of this conclusion is supported by molecular dynamics simulations.
Benchmarking monolayer MoS2 and WS2 field-effect transistors
Authors: Sebastian Amritanand , Pendurthi Rahul , Choudhury Tanushree H. , Redwing Joan M. , Das Saptarshi
Published: January 2021

Here we benchmark device-to-device variation in field-effect transistors (FETs) based on monolayer MoS2 and WS2 films grown using metal-organic chemical vapor deposition process. Our study involves 230 MoS2 FETs and 160 WS2 FETs with channel lengths ranging from 5 μm down to 100 nm. We use statistical measures to evaluate key FET performance indicators for benchmarking these two-dimensional (2D) transition metal dichalcogenide (TMD) monolayers against existing literature as well as ultra-thin body Si FETs. Our results show consistent performance of 2D FETs across 1 × 1 cm2 chips owing to high quality and uniform growth of these TMDs followed by clean transfer onto device substrates. We are able to demonstrate record high carrier mobility of 33 cm2 V−1 s−1 in WS2 FETs, which is a 1.5X improvement compared to the best reported in the literature. Our experimental demonstrations confirm the technological viability of 2D FETs in future integrated circuits.
The oncogenicity of tumor-derived mutant p53 is enhanced by the recruitment of PLK3
Authors: Vaughan Catherine A. , Singh Shilpa , Subler Mark A. , Windle Jolene J. , Inoue Kazushi , Fry Elizabeth A. , Pillappa Raghavendra , Grossman Steven R. , Windle Brad , Andrew Yeudall W. , Deb Swati Palit , Deb Sumitra
Published: January 2021

p53 mutations with single amino acid changes in cancer often lead to dominant oncogenic changes. Here, we have developed a mouse model of gain-of-function (GOF) p53-driven lung cancer utilizing conditionally active LSL p53-R172H and LSL K-Ras-G12D knock-in alleles that can be activated by Cre in lung club cells. Mutation of the p53 transactivation domain (TAD) (p53-L25Q/W26S/R172H) eliminating significant transactivation activity resulted in loss of tumorigenicity, demonstrating that transactivation mediated by or dependent on TAD is required for oncogenicity by GOF p53. GOF p53 TAD mutations significantly reduce phosphorylation of nearby p53 serine 20 (S20), which is a target for PLK3 phosphorylation. Knocking out PLK3 attenuated S20 phosphorylation along with transactivation and oncogenicity by GOF p53, indicating that GOF p53 exploits PLK3 to trigger its transactivation capability and exert oncogenic functions. Our data show a mechanistic involvement of PLK3 in mutant p53 pathway of oncogenesis.
Structural basis for a complex I mutation that blocks pathological ROS production
Authors: Yin Zhan , Burger Nils , Kula-Alwar Duvaraka , Aksentijević Dunja , Bridges Hannah R. , Prag Hiran A. , Grba Daniel N. , Viscomi Carlo , James Andrew M. , Mottahedin Amin , Krieg Thomas , Murphy Michael P. , Hirst Judy
Published: January 2021

Mitochondrial complex I is central to the pathological reactive oxygen species (ROS) production that underlies cardiac ischemia–reperfusion (IR) injury. ND6-P25L mice are homoplasmic for a disease-causing mtDNA point mutation encoding the P25L substitution in the ND6 subunit of complex I. The cryo-EM structure of ND6-P25L complex I revealed subtle structural changes that facilitate rapid conversion to the “deactive” state, usually formed only after prolonged inactivity. Despite its tendency to adopt the “deactive” state, the mutant complex is fully active for NADH oxidation, but cannot generate ROS by reverse electron transfer (RET). ND6-P25L mitochondria function normally, except for their lack of RET ROS production, and ND6-P25L mice are protected against cardiac IR injury in vivo. Thus, this single point mutation in complex I, which does not affect oxidative phosphorylation but renders the complex unable to catalyse RET, demonstrates the pathological role of ROS production by RET during IR injury.
Topological optical differentiator
Authors: Zhu Tengfeng , Guo Cheng , Huang Junyi , Wang Haiwen , Orenstein Meir , Ruan Zhichao , Fan Shanhui
Published: January 2021

Optical computing holds significant promise of information processing with ultrahigh speed and low power consumption. Recent developments in nanophotonic structures have generated renewed interests due to the prospects of performing analog optical computing with compact devices. As one prominent example, spatial differentiation has been demonstrated with nanophotonic structures and directly applied for edge detection in image processing. However, broadband isotropic two-dimensional differentiation, which is required in most imaging processing applications, has not been experimentally demonstrated yet. Here, we establish a connection between two-dimensional optical spatial differentiation and a nontrivial topological charge in the optical transfer function. Based on this connection, we experimentally demonstrate an isotropic two-dimensional differentiation with a broad spectral bandwidth, by using the simplest photonic device, i.e. a single unpatterned interface. Our work indicates that exploiting concepts from topological photonics can lead to new opportunities in optical computing.
Microthermal-induced subcellular-targeted protein damage in cells on plasmonic nanosilver-modified surfaces evokes a two-phase HSP-p97/VCP response
Authors: Mistrik Martin , Skrott Zdenek , Muller Petr , Panacek Ales , Hochvaldova Lucie , Chroma Katarina , Buchtova Tereza , Vandova Veronika , Kvitek Libor , Bartek Jiri
Published: January 2021

Despite proteotoxic stress and heat shock being implicated in diverse pathologies, currently no methodology to inflict defined, subcellular thermal damage exists. Here, we present such a single-cell method compatible with laser-scanning microscopes, adopting the plasmon resonance principle. Dose-defined heat causes protein damage in subcellular compartments, rapid heat-shock chaperone recruitment, and ensuing engagement of the ubiquitin–proteasome system, providing unprecedented insights into the spatiotemporal response to thermal damage relevant for degenerative diseases, with broad applicability in biomedicine. Using this versatile method, we discover that HSP70 chaperone and its interactors are recruited to sites of thermally damaged proteins within seconds, and we report here mechanistically important determinants of such HSP70 recruitment. Finally, we demonstrate a so-far unsuspected involvement of p97(VCP) translocase in the processing of heat-damaged proteins. Overall, we report an approach to inflict targeted thermal protein damage and its application to elucidate cellular stress-response pathways that are emerging as promising therapeutic targets.
Acoustic spectral hole-burning in a two-level system ensemble
Authors: Andersson G. , Bilobran A. L. O. , Scigliuzzo M. , de Lima M. M. , Cole J. H. , Delsing P.
Published: January 2021

Microscopic two-level system (TLS) defects at dielectric surfaces and interfaces are among the dominant sources of loss in superconducting quantum circuits, and their properties have been extensively probed using superconducting resonators and qubits. We report on spectroscopy of TLSs coupling to the strain field in a surface acoustic wave (SAW) resonator. The narrow free spectral range of the resonator allows for two-tone spectroscopy where a strong pump is applied at one resonance, while a weak signal is used to probe a different mode. We map the spectral hole burnt by the pump tone as a function of frequency and extract parameters of the TLS ensemble. Our results suggest that detuned acoustic pumping can be used to enhance the coherence of superconducting devices by saturating TLSs.
Burkholderia pseudomallei OMVs derived from infection mimicking conditions elicit similar protection to a live-attenuated vaccine
Authors: Baker Sarah M. , Settles Erik W. , Davitt Christopher , Gellings Patrick , Kikendall Nicole , Hoffmann Joseph , Wang Yihui , Bitoun Jacob , Lodrigue Kasi-Russell , Sahl Jason W. , Keim Paul , Roy Chad , McLachlan James , Morici Lisa A.
Published: January 2021

Burkholderia pseudomallei is a Gram-negative, facultative intracellular bacillus that causes the disease melioidosis. B. pseudomallei expresses a number of proteins that contribute to its intracellular survival in the mammalian host. We previously demonstrated that immunization with OMVs derived from B. pseudomallei grown in nutrient-rich media protects mice against lethal disease. Here, we evaluated if OMVs derived from B. pseudomallei grown under macrophage-mimicking growth conditions could be enriched with intracellular-stage proteins in order to improve the vaccine. We show that OMVs produced in this manner (M9 OMVs) contain proteins associated with intracellular survival yet are non-toxic to living cells. Immunization of mice provides significant protection against pulmonary infection similar to that achieved with a live attenuated vaccine and is associated with increased IgG, CD4+, and CD8+ T cells. OMVs possess inherent adjuvanticity and drive DC activation and maturation. These results indicate that M9 OMVs constitute a new promising vaccine against melioidosis.
Management of congenital nephrotic syndrome: consensus recommendations of the ERKNet-ESPN Working Group
Authors: Boyer Olivia , Schaefer Franz , Haffner Dieter , Bockenhauer Detlef , Hölttä Tuula , Bérody Sandra , Webb Hazel , Heselden Marie , Lipska-Zie˛tkiewicz Beata S. , Ozaltin Fatih , Levtchenko Elena , Vivarelli Marina
Published: January 2021

Congenital nephrotic syndrome (CNS) is a heterogeneous group of disorders characterized by nephrotic-range proteinuria, hypoalbuminaemia and oedema, which manifest in utero or during the first 3 months of life. The main cause of CNS is genetic defects in podocytes; however, it can also be caused, in rare cases, by congenital infections or maternal allo-immune disease. Management of CNS is very challenging because patients are prone to severe complications, such as haemodynamic compromise, infections, thromboses, impaired growth and kidney failure. In this consensus statement, experts from the European Reference Network for Kidney Diseases (ERKNet) and the European Society for Paediatric Nephrology (ESPN) summarize the current evidence and present recommendations for the management of CNS, including the use of renin–angiotensin system inhibitors, diuretics, anticoagulation and infection prophylaxis. Therapeutic management should be adapted to the clinical severity of the condition with the aim of maintaining intravascular euvolaemia and adequate nutrition, while preventing complications and preserving central and peripheral vessels. We do not recommend performing routine early nephrectomies but suggest that they are considered in patients with severe complications despite optimal conservative treatment, and before transplantation in patients with persisting nephrotic syndrome and/or a WT1-dominant pathogenic variant.
An Indo-Pacific coral spawning database
Authors: Baird Andrew H. , Guest James R. , Edwards Alasdair J. , Bauman Andrew G. , Bouwmeester Jessica , Mera Hanaka , Abrego David , Alvarez-Noriega Mariana , Babcock Russel C. , Barbosa Miguel B. , Bonito Victor , Burt John , Cabaitan Patrick C. , Chang Ching-Fong , Chavanich Suchana , Chen Chaolun A. , Chen Chieh-Jhen , Chen Wei-Jen , Chung Fung-Chen , Connolly Sean R. , Cumbo Vivian R. , Dornelas Maria , Doropoulos Christopher , Eyal Gal , Eyal-Shaham Lee , Fadli Nur , Figueiredo Joana , Flot Jean-François , Gan Sze-Hoon , Gomez Elizabeth , Graham Erin M. , Grinblat Mila , Gutiérrez-Isaza Nataly , Harii Saki , Harrison Peter L. , Hatta Masayuki , Ho Nina Ann Jin , Hoarau Gaetan , Hoogenboom Mia , Howells Emily J. , Iguchi Akira , Isomura Naoko , Jamodiong Emmeline A. , Jandang Suppakarn , Keyse Jude , Kitanobo Seiya , Kongjandtre Narinratana , Kuo Chao-Yang , Ligson Charlon , Lin Che-Hung , Low Jeffrey , Loya Yossi , Maboloc Elizaldy A. , Madin Joshua S. , Mezaki Takuma , Min Choo , Morita Masaya , Moya Aurelie , Neo Su-Hwei , Nitschke Matthew R. , Nojima Satoshi , Nozawa Yoko , Piromvaragorn Srisakul , Plathong Sakanan , Puill-Stephan Eneour , Quigley Kate , Ramirez-Portilla Catalina , Ricardo Gerard , Sakai Kazuhiko , Sampayo Eugenia , Shlesinger Tom , Sikim Leony , Simpson Chris , Sims Carrie A. , Sinniger Frederic , Spiji Davies A. , Tabalanza Tracy , Tan Chung-Hong , Terraneo Tullia I. , Torda Gergely , True James , Tun Karenne , Vicentuan Kareen , Viyakarn Voranop , Waheed Zarinah , Ward Selina , Willis Bette , Woods Rachael M. , Woolsey Erika S. , Yamamoto Hiromi H. , Yusuf Syafyudin
Published: January 2021

The discovery of multi-species synchronous spawning of scleractinian corals on the Great Barrier Reef in the 1980s stimulated an extraordinary effort to document spawning times in other parts of the globe. Unfortunately, most of these data remain unpublished which limits our understanding of regional and global reproductive patterns. The Coral Spawning Database (CSD) collates much of these disparate data into a single place. The CSD includes 6178 observations (3085 of which were unpublished) of the time or day of spawning for over 300 scleractinian species in 61 genera from 101 sites in the Indo-Pacific. The goal of the CSD is to provide open access to coral spawning data to accelerate our understanding of coral reproductive biology and to provide a baseline against which to evaluate any future changes in reproductive phenology.
Small changes in ball position at address cause a chain effect in golf swing
Authors: Kim Sung Eun , Lee Jangyun , Lee Sae Yong , Lee Hae-Dong , Shim Jae Kun , Lee Sung-Cheol
Published: January 2021

The purpose of this study was to investigate how the ball position along the mediolateral (M-L) direction of a golfer causes a chain effect in the ground reaction force, body segment and joint angles, and whole-body centre of mass during the golf swing. Twenty professional golfers were asked to complete five straight shots for each 5 different ball positions along M-L: 4.27 cm (ball diameter), 2.14 cm (ball radius), 0 cm (reference position at preferred ball position), – 2.14 cm, and – 4.27 cm, while their ground reaction force and body segment motions were captured. The dependant variables were calculated at 14 swing events from address to impact, and the differences between the ball positions were evaluated using Statistical Parametric Mapping. The left-sided ball positions at address showed a greater weight distribution on the left foot with a more open shoulder angle compared to the reference ball position, whereas the trend was reversed for the right-sided ball positions. These trends disappeared during the backswing and reappeared during the downswing. The whole-body centre of mass was also located towards the target for the left-sided ball positions throughout the golf swing compared to the reference ball position, whereas the trend was reversed for the right-sided ball positions. We have concluded that initial ball position at address can cause a series of chain effects throughout the golf swing.
Learning a reach trajectory based on binary reward feedback
Authors: van der Kooij Katinka , van Mastrigt Nina M. , Crowe Emily M. , Smeets Jeroen B. J.
Published: January 2021

Binary reward feedback on movement success is sufficient for learning some simple sensorimotor mappings in a reaching task, but not for some other tasks in which multiple kinematic factors contribute to performance. The critical condition for learning in more complex tasks remains unclear. Here, we investigate whether reward-based motor learning is possible in a multi-dimensional trajectory matching task and whether simplifying the task by providing feedback on one factor at a time (‘factorized feedback’) can improve learning. In two experiments, participants performed a trajectory matching task in which learning was measured as a reduction in the error. In Experiment 1, participants matched a straight trajectory slanted in depth. We factorized the task by providing feedback on the slant error, the length error, or on their composite. In Experiment 2, participants matched a curved trajectory, also slanted in depth. In this experiment, we factorized the feedback by providing feedback on the slant error, the curvature error, or on the integral difference between the matched and target trajectory. In Experiment 1, there was anecdotal evidence that participants learnt the multidimensional task. Factorization did not improve learning. In Experiment 2, there was anecdotal evidence the multidimensional task could not be learnt. We conclude that, within a complexity range, multiple kinematic factors can be learnt in parallel.
3D characterization of low optical absorption structures in large crystalline sapphire substrates for gravitational wave detectors
Authors: Marchiò Manuel , Leonardi Matteo , Bazzan Marco , Flaminio Raffaele
Published: January 2021

Very high-quality sapphire substrates are key elements of the cryogenic Japanese gravitational interferometer KAGRA, in which they are used to build the main mirrors, working as the test masses to sense the gravitational waves. To meet the extreme requirements of this system, the sapphire test masses must possess an extremely low optical absorption, which makes their study challenging using standard methods. In this paper, we illustrate the results obtained on two typical samples using a specialized absorption setup based on the technique of Photo-thermal Common-path Interferometry (PCI). Our system combines a very high sensitivity to small absorption features with the possibility to perform a full three-dimensional mapping of the sample volume. Our results elucidate how the ultra-low absorption variations inside the sample possess a structure that is probably inherited from the growth history of the sample. Some conclusions on the role of structural defects as preferential sites for the inclusion of absorbing centers are drawn.
Role of circulating endothelial cells in assessing the severity of systemic sclerosis and predicting its clinical worsening
Authors: Di Martino Maria Luisa , Frau Alessandra , Losa Francesca , Muggianu Emma , Mura Mario Nicola , Rotta Gianluca , Scotti Lorenza , Marongiu Francesco
Published: January 2021

Endothelial damage and fibro-proliferative vasculopathy of small vessels are pathological hallmarks of systemic sclerosis (SSc). The consequence is the detachment of resident elements that become circulating endothelial cells (CECs). The aim of our study was to evaluate the potential of CECs as biomarker in SSc. We enrolled 50 patients with limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) subset of SSc, who underwent clinical evaluation to establish the organ involvement. CECs were measured by flow-cytometry utilizing a polychromatic panel. An evident difference was observed in CEC counts comparing controls to SSc patients (median 10.5 vs. 152 cells/ml, p < 0.0001) and for the first time, between the two subsets of disease (median lcSSc 132 vs. dcSSc 716 CEC/ml, p < 0.0001). A significant correlation was established between CECs and some SSc clinical parameters, such as digital ulcers, skin and pulmonary involvement, presence of Scl-70 antibodies, nailfold videocapillaroscopy patterns and EUSTAR activity index. After 12 months, CECs correlated with clinical worsening of patients, showing that a number higher than 414 CEC/ml is a strong negative prognostic factor (RR 5.70). Our results indicate that CECs are a direct indicator of systemic vascular damage. Therefore, they can be used as a reliable marker of disease severity.
Impact of a toothpaste with microcrystalline hydroxyapatite on the occurrence of early childhood caries: a 1-year randomized clinical trial
Authors: Paszynska Elzbieta , Pawinska Malgorzata , Gawriolek Maria , Kaminska Inga , Otulakowska-Skrzynska Justyna , Marczuk-Kolada Grazyna , Rzatowski Szymon , Sokolowska Katarzyna , Olszewska Aneta , Schlagenhauf Ulrich , May Theodor W. , Amaechi Bennett T. , Luczaj-Cepowicz Elzbieta
Published: January 2021

The aim of this trial was to determine whether a toothpaste with microcrystalline hydroxyapatite is not inferior to a fluoride toothpaste in prevention of caries in children. This double-blinded randomized control trial compared two toothpastes regarding the occurrence of caries lesions using International Caries Detection and Assessment System (ICDAS) ≥ code 1 on the primary dentition within 336 days. The test group used a fluoride-free hydroxyapatite toothpaste three times daily while control group used a toothpaste with fluoride. 207 children were included in the intention-to-treat analysis; 177 of them finished the study per protocol. An increase in caries ICDAS ≥ code 1 per tooth was observed in 72.7% of the hydroxyapatite-group (n = 88), compared with 74.2% of the fluoride-group (n = 89). The exact one-sided upper 95% confidence limit for the difference in proportion of participants with ICDAS increase ≥ 1 (-1.4%) was 9.8%, which is below the non-inferiority margin of 20% demonstrating non-inferiority of hydroxyapatite compared to the fluoride control toothpaste. This RCT showed for the first time, that in children, the impact of the daily use of a toothpaste with microcrystalline hydroxyapatite on enamel caries progression in the primary dentition is not inferior to a fluoride control toothpaste (Clinical Trials NCT03553966).
An integrated set-up for ex vivo characterisation of biaxial murine artery biomechanics under pulsatile conditions
Authors: van der Bruggen Myrthe M. , Reesink Koen D. , Spronck Paul J. M. , Bitsch Nicole , Hameleers Jeroen , Megens Remco T. A. , Schalkwijk Casper G. , Delhaas Tammo , Spronck Bart
Published: January 2021

Ex vivo characterisation of arterial biomechanics enables detailed discrimination of the various cellular and extracellular contributions to arterial stiffness. However, ex vivo biomechanical studies are commonly performed under quasi-static conditions, whereas dynamic biomechanical behaviour (as relevant in vivo) may differ substantially. Hence, we aim to (1) develop an integrated set-up for quasi-static and dynamic biaxial biomechanical testing, (2) quantify set-up reproducibility, and (3) illustrate the differences in measured arterial stiffness between quasi-static and dynamic conditions. Twenty-two mouse carotid arteries were mounted between glass micropipettes and kept fully vasodilated. While recording pressure, axial force (F), and inner diameter, arteries were exposed to (1) quasi-static pressure inflation from 0 to 200 mmHg; (2) 300 bpm dynamic pressure inflation (peaking at 80/120/160 mmHg); and (3) axial stretch (λz) variation at constant pressures of 10/60/100/140/200 mmHg. Measurements were performed in duplicate. Single-point pulse wave velocities (PWV; Bramwell-Hill) and axial stiffness coefficients (cax = dF/dλz) were calculated at the in vivo value of λz. Within-subject coefficients of variation were ~ 20%. Dynamic PWVs were consistently higher than quasi-static PWVs (p < 0.001); cax increased with increasing pressure. We demonstrated the feasibility of ex vivo biomechanical characterisation of biaxially-loaded murine carotid arteries under pulsatile conditions, and quantified reproducibility allowing for well-powered future study design.
Measuring myocardial extracellular volume of the right ventricle in patients with congenital heart disease
Authors: Al-Wakeel-Marquard Nadya , Ferreira da Silva Tiago , Jeuthe Sarah , Rastin Sanaz , Muench Frédéric , O h-Ici Darach , Yilmaz Sevim , Berger Felix , Kuehne Titus , Messroghli Daniel R.
Published: January 2021

The right ventricle´s (RV) characteristics—thin walls and trabeculation—make it challenging to evaluate extracellular volume (ECV). We aimed to assess the feasibility of RV ECV measurements in congenital heart disease (CHD), and to introduce a novel ECV analysis tool. Patients (n = 39) and healthy controls (n = 17) underwent cardiovascular magnetic resonance T1 mapping in midventricular short axis (SAX) and transverse orientation (TRANS). Regions of interest (ROIs) were evaluated with regard to image quality and maximum RV wall thickness per ROI in pixels. ECV from plane ROIs was compared with values obtained with a custom-made tool that derives the mean T1 values from a “line of interest” (LOI) centered in the RV wall. In CHD, average image quality was good (no artifacts in the RV, good contrast between blood/myocardium), and RV wall thickness was 1–2 pixels. RV ECV was not quantifiable in 4/39 patients due to insufficient contrast or wall thickness < 1 pixel. RV myocardium tended to be more clearly delineated in SAX than TRANS. ECV from ROIs and corresponding LOIs correlated strongly in both directions (SAX/TRANS: r = 0.97/0.87, p < 0.001, respectively). In conclusion, RV ECV can be assessed if image quality allows sufficient distinction between myocardium and blood, and RV wall thickness per ROI is ≥ 1 pixel. T1 maps in SAX are recommended for RV ECV analysis. LOI application simplifies RV ECV measurements.
Mechanomyography and acceleration show interlimb asymmetries in Parkinson patients without tremor compared to controls during a unilateral motor task
Authors: Schaefer Laura V. , Löffler Nils , Klein Julia , Bittmann Frank N.
Published: January 2021

The mechanical muscular oscillations are rarely the objective of investigations regarding the identification of a biomarker for Parkinson’s disease (PD). Therefore, the aim of this study was to investigate whether or not this specific motor output differs between PD patients and controls. The novelty is that patients without tremor are investigated performing a unilateral isometric motor task. The force of armflexors and the forearm acceleration (ACC) were recorded as well as the mechanomyography of the biceps brachii (MMGbi), brachioradialis (MMGbra) and pectoralis major (MMGpect) muscles using a piezoelectric-sensor-based system during a unilateral motor task at 70% of the MVIC. The frequency, a power-frequency-ratio, the amplitude variation, the slope of amplitudes and their interlimb asymmetries were analysed. The results indicate that the oscillatory behavior of muscular output in PD without tremor deviates from controls in some parameters: Significant differences appeared for the power-frequency-ratio (p = 0.001, r = 0.43) and for the amplitude variation (p = 0.003, r = 0.34) of MMGpect. The interlimb asymmetries differed significantly concerning the power-frequency-ratio of MMGbi (p = 0.013, r = 0.42) and MMGbra (p = 0.048, r = 0.39) as well as regarding the mean frequency (p = 0.004, r = 0.48) and amplitude variation of MMGpect (p = 0.033, r = 0.37). The mean (M) and variation coefficient (CV) of slope of ACC differed significantly (M: p = 0.022, r = 0.33; CV: p = 0.004, r = 0.43). All other parameters showed no significant differences between PD and controls. It remains open, if this altered mechanical muscular output is reproducible and specific for PD.
The role of gene to gene interaction in the breast’s genomic signature of pregnancy
Authors: Gutiérrez-Díez Pedro J. , Gomez-Pilar Javier , Hornero Roberto , Martínez-Rodríguez Julia , López-Marcos Miguel A. , Russo Jose
Published: January 2021

Full-term pregnancy at an early age confers long-term protection against breast cancer. Published data shows a specific transcriptomic profile controlling chromatin remodeling that could play a relevant role in the pregnancy-induced protection. This process of chromatin remodeling, induced by the breast differentiation caused by the first full-term pregnancy, has mainly been measured by the expression level of genes individually considered. However, genes equally expressed during the process of chromatin remodeling may behave differently in their interaction with other genes. These changes at the gene cluster level could constitute an additional dimension of chromatin remodeling and therefore of the pregnancy-induced protection. In this research, we apply Information and Graph Theories, Differential Co-expression Network Analysis, and Multiple Regression Analysis, specially designed to examine structural and informational aspects of data sets, to analyze this question. Our findings demonstrate that, independently of the changes in the gene expression at the individual level, there are significant changes in gene–gene interactions and gene cluster behaviors. These changes indicate that the parous breast, through the process of early full-term pregnancy, generates more modules in the networks, with higher density, and a genomic structure performing additional and more complex functions than those found in the nulliparous breast.
Verifying explainability of a deep learning tissue classifier trained on RNA-seq data
Authors: Yap Melvyn , Johnston Rebecca L. , Foley Helena , MacDonald Samual , Kondrashova Olga , Tran Khoa A. , Nones Katia , Koufariotis Lambros T. , Bean Cameron , Pearson John V. , Trzaskowski Maciej , Waddell Nicola
Published: January 2021

For complex machine learning (ML) algorithms to gain widespread acceptance in decision making, we must be able to identify the features driving the predictions. Explainability models allow transparency of ML algorithms, however their reliability within high-dimensional data is unclear. To test the reliability of the explainability model SHapley Additive exPlanations (SHAP), we developed a convolutional neural network to predict tissue classification from Genotype-Tissue Expression (GTEx) RNA-seq data representing 16,651 samples from 47 tissues. Our classifier achieved an average F1 score of 96.1% on held-out GTEx samples. Using SHAP values, we identified the 2423 most discriminatory genes, of which 98.6% were also identified by differential expression analysis across all tissues. The SHAP genes reflected expected biological processes involved in tissue differentiation and function. Moreover, SHAP genes clustered tissue types with superior performance when compared to all genes, genes detected by differential expression analysis, or random genes. We demonstrate the utility and reliability of SHAP to explain a deep learning model and highlight the strengths of applying ML to transcriptome data.
Water use of Prosopis juliflora and its impacts on catchment water budget and rural livelihoods in Afar Region, Ethiopia
Authors: Shiferaw Hailu , Alamirew Tena , Dzikiti Sebinasi , Bewket Woldeamlak , Zeleke Gete , Schaffner Urs
Published: January 2021

Dense impenetrable thickets of invasive trees and shrubs compete with other water users and thus disrupt ecosystem functioning and services. This study assessed water use by the evergreenProsopis juliflora,one of the dominant invasive tree species in semi-arid and arid ecosystems in the tropical regions of Eastern Africa. The objectives of the study were to (1) analyze the seasonal water use patterns ofP. juliflorain various locations in Afar Region, Ethiopia, (2) up-scale the water use from individual tree transpiration and stand evapotranspiration (ET) to the entire invaded area, and 3) estimate the monetary value of water lost due to the invasion. The sap flow rates of individualP. julifloratrees were measured using the heat ratio method while stand ET was quantified using the eddy covariance method. Transpiration by individual trees ranged from 1–36 L/day, with an average of 7 L of water per tree per day. The daily average transpiration of aProsopistree was about 3.4 (± 0.5) mm and the daily average ET of a denseProsopisstand was about 3.7 (± 1.6) mm. Using a fractional cover map ofP. juliflora(over an area of 1.18 million ha), water use ofP. juliflorain Afar Region was estimated to be approximately 3.1–3.3 billion m3/yr. This volume of water would be sufficient to irrigate about 460,000 ha of cotton or 330,000 ha of sugar cane, the main crops in the area, which would generate an estimated net benefit of approximately US$ 320 million and US$ 470 million per growing season from cotton and sugarcane, respectively. Hence,P. juliflorainvasion in the Afar Region has serious impacts on water availability and on the provision of other ecosystem services and ultimately on rural livelihoods.
Custom, spray coated receive coils for magnetic resonance imaging
Authors: Zamarayeva A. M. , Gopalan K. , Corea J. R. , Liu M. Z. , Pang K. , Lustig M. , Arias A. C.
Published: January 2021

We have developed a process for fabricating patient specific Magnetic Resonance Imaging (MRI) Radio-frequency (RF) receive coil arrays using additive manufacturing. Our process involves spray deposition of silver nanoparticle inks and dielectric materials onto 3D printed substrates to form high-quality resonant circuits. In this paper, we describe the material selection and characterization, process optimization, and design and testing of a prototype 4-channel neck array for carotid imaging. We show that sprayed polystyrene can form a low loss dielectric layer in a parallel plate capacitor. We also demonstrate that by using sprayed silver nanoparticle ink as conductive traces, our devices are still dominated by sample noise, rather than material losses. These results are critical for maintaining high Signal-to-Noise-Ratio (SNR) in clinical settings. Finally, our prototype patient specific coil array exhibits higher SNR (5 × in the periphery, 1.4 × in the center) than a commercially available array designed to fit the majority of subjects when tested on our custom neck phantom. 3D printed substrates ensure an optimum fit to complex body parts, improve diagnostic image quality, and enable reproducible placement on subjects.
Upscaling the porosity–permeability relationship of a microporous carbonate for Darcy-scale flow with machine learning
Authors: Menke H. P. , Maes J. , Geiger S.
Published: January 2021

The permeability of a pore structure is typically described by stochastic representations of its geometrical attributes (e.g. pore-size distribution, porosity, coordination number). Database-driven numerical solvers for large model domains can only accurately predict large-scale flow behavior when they incorporate upscaled descriptions of that structure. The upscaling is particularly challenging for rocks with multimodal porosity structures such as carbonates, where several different type of structures (e.g. micro-porosity, cavities, fractures) are interacting. It is the connectivity both within and between these fundamentally different structures that ultimately controls the porosity–permeability relationship at the larger length scales. Recent advances in machine learning techniques combined with both numerical modelling and informed structural analysis have allowed us to probe the relationship between structure and permeability much more deeply. We have used this integrated approach to tackle the challenge of upscaling multimodal and multiscale porous media. We present a novel method for upscaling multimodal porosity–permeability relationships using machine learning based multivariate structural regression. A micro-CT image of Estaillades limestone was divided into small 603 and 1203 sub-volumes and permeability was computed using the Darcy–Brinkman–Stokes (DBS) model. The microporosity–porosity–permeability relationship from Menke et al. (Earth Arxiv, https://doi.org/10.31223/osf.io/ubg6p, 2019) was used to assign permeability values to the cells containing microporosity. Structural attributes (porosity, phase connectivity, volume fraction, etc.) of each sub-volume were extracted using image analysis tools and then regressed against the solved DBS permeability using an Extra-Trees regression model to derive an upscaled porosity–permeability relationship. Ten test cases of 3603 voxels were then modeled using Darcy-scale flow with this machine learning predicted upscaled porosity–permeability relationship and benchmarked against full DBS simulations, a numerically upscaled Darcy flow model, and a Kozeny–Carman model. All numerical simulations were performed using GeoChemFoam, our in-house open source pore-scale simulator based on OpenFOAM. We found good agreement between the full DBS simulations and both the numerical and machine learning upscaled models, with the machine learning model being 80 times less computationally expensive. The Kozeny–Carman model was a poor predictor of upscaled permeability in all cases.
A risk progression breast epithelial 3D culture model reveals Cx43/hsa_circ_0077755/miR-182 as a biomarker axis for heightened risk of breast cancer initiation
Authors: Naser Al Deen Nataly , Atallah Lanman Nadia , Chittiboyina Shirisha , Lelièvre Sophie , Nasr Rihab , Nassar Farah , Zu Dohna Heinrich , AbouHaidar Mounir , Talhouk Rabih
Published: January 2021

mRNA-circRNA-miRNAs axes have been characterized in breast cancer, but not as risk-assessment axes for tumor initiation in early-onset breast cancer that is increasing drastically worldwide. To address this gap, we performed circular RNA (circRNA) microarrays and microRNA (miRNA) sequencing on acini of HMT-3522 S1 (S1) breast epithelial risk-progression culture model in 3D and chose an early-stage population miRNome for a validation cohort. Nontumorigenic S1 cells form fully polarized epithelium while pretumorigenic counterparts silenced for gap junction Cx43 (Cx43-KO-S1) lose epithelial polarity, multilayer and mimic premalignant in vivo mammary epithelial morphology. Here, 121 circRNAs and 65 miRNAs were significantly dysregulated in response to Cx43 silencing in cultured epithelia and 15 miRNAs from the patient cohort were involved in epithelial polarity disruption. Focusing on the possible sponging activity of the validated circRNAs to their target miRNAs, we found all miRNAs to be highly enriched in cancer-related pathways and cross-compared their dysregulation to actual miRNA datasets from the cultured epithelia and the patient validation cohort. We present the involvement of gap junction in post-transcriptional axes and reveal Cx43/hsa_circ_0077755/miR-182 as a potential biomarker signature axis for heightened-risk of breast cancer initiation, and that its dysregulation patterns might predict prognosis along breast cancer initiation and progression.
The unusual isolation of carnobacteria in eyes of healthy salmonids in high-mountain lakes
Authors: Pastorino Paolo , Colussi Silvia , Pizzul Elisabetta , Varello Katia , Menconi Vasco , Mugetti Davide , Tomasoni Mattia , Esposito Giuseppe , Bertoli Marco , Bozzetta Elena , Dondo Alessandro , Acutis Pier Luigi , Prearo Marino
Published: January 2021

Carnobacteria are common bacteria in cold and temperate environments; they are also reported during fish mortality events. In a previous study, carnobacteria were isolated from the eyes of healthy wild salmonids from a high-mountain lake. To better understand these findings, salmonids were captured from three high-mountain lakes (Lower and Upper Balma Lake, Rouen Lake; northwest Italy) during August 2019 and subjected to bacteriological and histological examination. Although all were healthy, 8.7% (Lower Balma Lake), 24% (Upper Balma Lake), and 32.6% (Rouen Lake) were positive for carnobacteria colonization of the eyes. A Trojan-horse effect was hypothesized to explain carnobacteria isolation in the eye. This immune-escaping macrophage-mediated mechanism has been identified in other Gram-positive bacteria. Biochemical, molecular, and phylogenetic analysis were carried out on isolated bacteria (Carnobacterium maltaromaticum and C. divergens). Based on previous references for carnobacteria isolated from fish, C. maltaromaticum strains were tested for the pisA precursor gene of the bacteriocin piscicolin 126. Carnobacterium maltaromaticum strains were found to display genotypic heterogeneity and a low percentage of pisA positive amplification. Features of geomorphology, geographic isolation, and microbiota common to the three lakes are thought to be possibly related to our findings. Moreover, terrestrial insects collected from the lake shoreline and the stomach contents were screened for the presence of carnobacteria. The salmonids in these high-mountain environments feed mainly on terrestrial insects, which are considered possible vectors for carnobacteria that might catabolize the exoskeleton chitin. All insects tested negative for carnobacteria, but as a small number of samples were analyzed, their role as possible vectors of infection cannot be excluded. Further studies are needed to corroborate our research hypothesis.