bluuebunny/crossref_metadata_2025 huggingface dataset:
Mutational landscape of normal epithelial cells in Lynch Syndrome patients
Authors: Lee Bernard C. H. , Robinson Philip S. , Coorens Tim H. H. , Yan Helen H. N. , Olafsson Sigurgeir , Lee-Six Henry , Sanders Mathijs A. , Siu Hoi Cheong , Hewinson James , Yue Sarah S. K. , Tsui Wai Yin , Chan Annie S. Y. , Chan Anthony K. W. , Ho Siu Lun , Campbell Peter J. , Martincorena Inigo , Buczacki Simon J. A. , Yuen Siu Tsan , Leung Suet Yi , Stratton Michael R.
Published: May 2022

Lynch Syndrome (LS) is an autosomal dominant disease conferring a high risk of colorectal cancer due to germline heterozygous mutations in a DNA mismatch repair (MMR) gene. Although cancers in LS patients show elevated somatic mutation burdens, information on mutation rates in normal tissues and understanding of the trajectory from normal to cancer cell is limited. Here we whole genome sequence 152 crypts from normal and neoplastic epithelial tissues from 10 LS patients. In normal tissues the repertoire of mutational processes and mutation rates is similar to that found in wild type individuals. A morphologically normal colonic crypt with an increased mutation burden and MMR deficiency-associated mutational signatures is identified, which may represent a very early stage of LS pathogenesis. Phylogenetic trees of tumour crypts indicate that the most recent ancestor cell of each tumour is already MMR deficient and has experienced multiple cycles of clonal evolution. This study demonstrates the genomic stability of epithelial cells with heterozygous germline MMR gene mutations and highlights important differences in the pathogenesis of LS from other colorectal cancer predisposition syndromes.
A Middle Pleistocene Denisovan molar from the Annamite Chain of northern Laos
Authors: Demeter Fabrice , Zanolli Clément , Westaway Kira E. , Joannes-Boyau Renaud , Duringer Philippe , Morley Mike W. , Welker Frido , Rüther Patrick L. , Skinner Matthew M. , McColl Hugh , Gaunitz Charleen , Vinner Lasse , Dunn Tyler E. , Olsen Jesper V. , Sikora Martin , Ponche Jean-Luc , Suzzoni Eric , Frangeul Sébastien , Boesch Quentin , Antoine Pierre-Olivier , Pan Lei , Xing Song , Zhao Jian-Xin , Bailey Richard M. , Boualaphane Souliphane , Sichanthongtip Phonephanh , Sihanam Daovee , Patole-Edoumba Elise , Aubaile Françoise , Crozier Françoise , Bourgon Nicolas , Zachwieja Alexandra , Luangkhoth Thonglith , Souksavatdy Viengkeo , Sayavongkhamdy Thongsa , Cappellini Enrico , Bacon Anne-Marie , Hublin Jean-Jacques , Willerslev Eske , Shackelford Laura
Published: May 2022

The Pleistocene presence of the genusHomoin continental Southeast Asia is primarily evidenced by a sparse stone tool record and rare human remains. Here we report a Middle Pleistocene hominin specimen from Laos, with the discovery of a molar from the Tam Ngu Hao 2 (Cobra Cave) limestone cave in the Annamite Mountains. The age of the fossil-bearing breccia ranges between 164–131 kyr, based on the Bayesian modelling of luminescence dating of the sedimentary matrix from which it was recovered, U-series dating of an overlying flowstone, and U-series–ESR dating of associated faunal teeth. Analyses of the internal structure of the molar in tandem with palaeoproteomic analyses of the enamel indicate that the tooth derives from a young, likely female,Homoindividual. The close morphological affinities with the Xiahe specimen from China indicate that they belong to the same taxon and that Tam Ngu Hao 2 most likely represents a Denisovan.
Nucleotide-amino acid π-stacking interactions initiate photo cross-linking in RNA-protein complexes
Authors: Knörlein Anna , Sarnowski Chris P. , de Vries Tebbe , Stoltz Moritz , Götze Michael , Aebersold Ruedi , Allain Frédéric H.-T. , Leitner Alexander , Hall Jonathan
Published: May 2022

Photo-induced cross-linking is a mainstay technique to characterize RNA-protein interactions. However, UV-induced cross-linking between RNA and proteins at “zero-distance” is poorly understood. Here, we investigate cross-linking of the RBFOX alternative splicing factor with its hepta-ribonucleotide binding element as a model system. We examine the influence of nucleobase, nucleotide position and amino acid composition using CLIR-MS technology (crosslinking-of-isotope-labelled-RNA-and-tandem-mass-spectrometry), that locates cross-links on RNA and protein with site-specific resolution. Surprisingly, cross-linking occurs only at nucleotides that are π-stacked to phenylalanines. Notably, this π-stacking interaction is also necessary for the amino-acids flanking phenylalanines to partake in UV-cross-linking. We confirmed these observations in several published datasets where cross-linking sites could be mapped to a high resolution structure. We hypothesize that π-stacking to aromatic amino acids activates cross-linking in RNA-protein complexes, whereafter nucleotide and peptide radicals recombine. These findings will facilitate interpretation of cross-linking data from structural studies and from genome-wide datasets generated using CLIP (cross-linking-and-immunoprecipitation) methods.
Drought assessment has been outpaced by climate change: empirical arguments for a paradigm shift
Authors: Hoylman Zachary H. , Bocinsky R. Kyle , Jencso Kelsey G.
Published: May 2022

Despite the acceleration of climate change, erroneous assumptions of climate stationarity are still inculcated in the management of water resources in the United States (US). The US system for drought detection, which triggers billions of dollars in emergency resources, adheres to this assumption with preference towards 60-year (or longer) record lengths for drought characterization. Using observed data from 1,934 Global Historical Climate Network (GHCN) sites across the US, we show that conclusions based on long climate records can substantially bias assessment of drought severity. Bias emerges by assuming that conditions from the early and mid 20th century are as likely to occur in today’s climate. Numerical simulations reveal that drought assessment error is relatively low with limited climatology lengths (~30 year) and that error increases with longer record lengths where climate is changing rapidly. We assert that non-stationarity in climate must be accounted for in contemporary assessments to more accurately portray present drought risk.
N-type fast inactivation of a eukaryotic voltage-gated sodium channel
Authors: Zhang Jiangtao , Shi Yiqiang , Fan Junping , Chen Huiwen , Xia Zhanyi , Huang Bo , Jiang Juquan , Gong Jianke , Huang Zhuo , Jiang Daohua
Published: May 2022

Voltage-gated sodium (NaV) channels initiate action potentials. Fast inactivation of NaV channels, mediated by an Ile-Phe-Met motif, is crucial for preventing hyperexcitability and regulating firing frequency. Here we present cryo-electron microscopy structure of NaVEh from the coccolithophore Emiliania huxleyi, which reveals an unexpected molecular gating mechanism for NaV channel fast inactivation independent of the Ile-Phe-Met motif. An N-terminal helix of NaVEh plugs into the open activation gate and blocks it. The binding pose of the helix is stabilized by multiple electrostatic interactions. Deletion of the helix or mutations blocking the electrostatic interactions completely abolished the fast inactivation. These strong interactions enable rapid inactivation, but also delay recovery from fast inactivation, which is ~160-fold slower than human NaV channels. Together, our results provide mechanistic insights into fast inactivation of NaVEh that fundamentally differs from the conventional local allosteric inhibition, revealing both surprising structural diversity and functional conservation of ion channel inactivation.
Mineralogical control on methylotrophic methanogenesis and implications for cryptic methane cycling in marine surface sediment
Authors: Xiao Ke-Qing , Moore Oliver W. , Babakhani Peyman , Curti Lisa , Peacock Caroline L.
Published: May 2022

Minerals are widely proposed to protect organic carbon from degradation and thus promote the persistence of organic carbon in soils and sediments, yet a direct link between mineral adsorption and retardation of microbial remineralisation is often presumed and a mechanistic understanding of the protective preservation hypothesis is lacking. We find that methylamines, the major substrates for cryptic methane production in marine surface sediment, are strongly adsorbed by marine sediment clays, and that this adsorption significantly reduces their concentrations in the dissolved pool (up to 40.2 ± 0.2%). Moreover, the presence of clay minerals slows methane production and reduces final methane produced (up to 24.9 ± 0.3%) by a typical methylotrophic methanogen—Methanococcoides methylutens TMA-10. Near edge X-ray absorption fine structure spectroscopy shows that reversible adsorption and occlusive protection of methylamines in clay interlayers are responsible for the slow-down and reduction in methane production. Here we show that mineral-OC interactions strongly control methylotrophic methanogenesis and potentially cryptic methane cycling in marine surface sediments.
Histone H1 binding to nucleosome arrays depends on linker DNA length and trajectory
Authors: Dombrowski Marco , Engeholm Maik , Dienemann Christian , Dodonova Svetlana , Cramer Patrick
Published: May 2022

Throughout the genome, nucleosomes often form regular arrays that differ in nucleosome repeat length (NRL), occupancy of linker histone H1 and transcriptional activity. Here, we report cryo-EM structures of human H1-containing tetranucleosome arrays with four physiologically relevant NRLs. The structures show a zig-zag arrangement of nucleosomes, with nucleosomes 1 and 3 forming a stack. H1 binding to stacked nucleosomes depends on the NRL, whereas H1 always binds to the non-stacked nucleosomes 2 and 4. Short NRLs lead to altered trajectories of linker DNA, and these altered trajectories sterically impair H1 binding to the stacked nucleosomes in our structures. As the NRL increases, linker DNA trajectories relax, enabling H1 contacts and binding. Our results provide an explanation for why arrays with short NRLs are depleted of H1 and suited for transcription, whereas arrays with long NRLs show full H1 occupancy and can form transcriptionally silent heterochromatin regions.
A benchmark dataset for Hydrogen Combustion
Authors: Guan Xingyi , Das Akshaya , Stein Christopher J. , Heidar-Zadeh Farnaz , Bertels Luke , Liu Meili , Haghighatlari Mojtaba , Li Jie , Zhang Oufan , Hao Hongxia , Leven Itai , Head-Gordon Martin , Head-Gordon Teresa
Published: May 2022

The generation of reference data for deep learning models is challenging for reactive systems, and more so for combustion reactions due to the extreme conditions that create radical species and alternative spin states during the combustion process. Here, we extend intrinsic reaction coordinate (IRC) calculations with ab initio MD simulations and normal mode displacement calculations to more extensively cover the potential energy surface for 19 reaction channels for hydrogen combustion. A total of ∼290,000 potential energies and ∼1,270,000 nuclear force vectors are evaluated with a high quality range-separated hybrid density functional, ωB97X-V, to construct the reference data set, including transition state ensembles, for the deep learning models to study hydrogen combustion reaction.
Quantifying yeast colony morphologies with feature engineering from time-lapse photography
Authors: Goldschmidt Andy , Kunert-Graf James , Scott Adrian C. , Tan Zhihao , Dudley Aimée M. , Kutz J. Nathan
Published: May 2022

Baker’s yeast (Saccharomyces cerevisiae) is a model organism for studying the morphology that emerges at the scale of multi-cell colonies. To look at how morphology develops, we collect a dataset of time-lapse photographs of the growth of different strains of S. cerevisiae. We discuss the general statistical challenges that arise when using time-lapse photographs to extract time-dependent features. In particular, we show how texture-based feature engineering and representative clustering can be successfully applied to categorize the development of yeast colony morphology using our dataset. The Local binary pattern (LBP) from image processing is used to score the surface texture of colonies. This texture score develops along a smooth trajectory during growth. The path taken depends on how the morphology emerges. A hierarchical clustering of the colonies is performed according to their texture development trajectories. The clustering method is designed for practical interpretability; it obtains the best representative colony image for any hierarchical cluster.
Fundamental aspects of long-acting tenofovir alafenamide delivery from subdermal implants for HIV prophylaxis
Authors: Gunawardana Manjula , Remedios-Chan Mariana , Sanchez Debbie , Webster Simon , Castonguay Amalia E. , Webster Paul , Buser Christopher , Moss John A. , Trinh MyMy , Beliveau Martin , Hendrix Craig W. , Marzinke Mark A. , Tuck Michael , Caprioli Richard M. , Reyzer Michelle L. , Kuo Joseph , Gallay Philippe A. , Baum Marc M.
Published: May 2022

Global efforts aimed at preventing human immunodeficiency virus type one (HIV-1) infection in vulnerable populations appear to be stalling, limiting our ability to control the epidemic. Long-acting, controlled drug administration from subdermal implants holds significant potential by reducing the compliance burden associated with frequent dosing. We, and others, are exploring the development of complementary subdermal implant technologies delivering the potent prodrug, tenofovir alafenamide (TAF). The current report addresses knowledge gaps in the preclinical pharmacology of long-acting, subdermal TAF delivery using several mouse models. Systemic drug disposition during TAF implant dosing was explained by a multi-compartment pharmacokinetic (PK) model. Imaging mass spectrometry was employed to characterize the spatial distribution of TAF and its principal five metabolites in local tissues surrounding the implant. Humanized mouse studies determined the effective TAF dose for preventing vaginal and rectal HIV-1 acquisition. Our results represent an important step in the development of a safe and effective TAF implant for HIV-1 prevention.
99mTc-NTP 15-5 is a companion radiotracer for assessing joint functional response to sprifermin (rhFGF-18) in a murine osteoarthritis model
Authors: Briat Arnaud , Jacques Claire , Malige Mélodie , Sudre Laure , Nourissat Geoffroy , Auzeloux Philippe , Guehring Hans , Cachin Florent , Berenbaum Francis , Miot-Noirault Elisabeth
Published: May 2022

With the emergence of disease modifying osteoarthritis drugs (DMOAD), imaging methods to quantitatively demonstrate their efficacy and to monitor osteoarthritis progression at the functional level are urgently needed. Our group showed that articular cartilage can be quantitatively assessed in nuclear medicine imaging by our radiotracer 99mTc-NTP 15-5 targeting cartilage proteoglycans. In this work, surgically induced DMM mice were treated with sprifermin or saline. We investigated cartilage remodelling in the mice knees by 99mTc-NTP 15-5 SPECT-CT imaging over 24 weeks after surgery, as wells as proteoglycan biochemical assays. OA alterations were scored by histology according to OARSI guidelines. A specific accumulation of 99mTc-NTP 15-5 in cartilage joints was evidenced in vivo by SPECT-CT imaging as early as 30 min post-iv injection. In DMM, 99mTc-NTP 15-5 accumulation in cartilage within the operated joints, relative to contralateral ones, was observed to initially increase then decrease as pathology progressed. Under sprifermin, 99mTc-NTP 15-5 uptake in pathological knees was significantly increased compared to controls, at 7-, 12- and 24-weeks, and consistent with proteoglycan increase measured 5 weeks post-surgery, as a sign of cartilage matrix remodelling. Our work highlights the potential of 99mTc-NTP 15-5 as an imaging-based companion to monitor cartilage remodelling in OA and DMOAD response.
A novel ATG5 interaction with Ku70 potentiates DNA repair upon genotoxic stress
Authors: Demirbag-Sarikaya Sinem , Akkoc Yunus , Turgut Sıla , Erbil-Bilir Secil , Kocaturk Nur Mehpare , Dengjel Joern , Gozuacik Devrim
Published: May 2022

The maintenance of cellular homeostasis in living organisms requires a balance between anabolic and catabolic reactions. Macroautophagy (autophagy herein) is determined as one of the major catabolic reactions. Autophagy is an evolutionarily conserved stress response pathway that is activated by various insults including DNA damage. All sorts of damage to DNA potentially cause loss of genetic information and trigger genomic instability. Most of these lesions are repaired by the activation of DNA damage response following DNA repair mechanisms. Here we describe, a novel protein complex containing the autophagy protein ATG5 and the non-homologous end-joining repair system proteins. We discovered for the first time that ATG5 interacted with both Ku80 (XRCC5) and Ku70 (XRCC6). This novel interaction is facilitated mainly via Ku70. Our results suggest that this interaction is dynamic and enhanced upon genotoxic stresses. Strikingly, we identified that ATG5-Ku70 interaction is necessary for DNA repair and effective recovery from genotoxic stress. Therefore, our results are demonstrating a novel, direct, dynamic, and functional interaction between ATG5 and Ku70 proteins that plays a crucial role in DNA repair under genotoxic stress conditions.
Overnutrition is a significant component of food waste and has a large environmental impact
Authors: Franco Silvio , Barbanera Marco , Moscetti Roberto , Cicatiello Clara , Secondi Luca , Massantini Riccardo
Published: May 2022

Food waste and obesity and overweight conditions are both linked to the unsustainability of current food systems. This article argues that overnutrition should be considered a form of food waste and it provides a first estimation of the quantity of food over-consumed in Italy. This is done by calculating the excess calories consumed by obese and overweight people and converting them into food quantities by comparison with a typical Italian diet. The total quantity of food consumed in excess by Italian citizens due to overnutrition is calculated as 1.553 million tonnes per year, which is comparable to the current national household food waste assessments. The environmental impact arising from production and consumption of this food accounts for 6.15 Mt of CO2-eq per year, as estimated by a Life Cycle Analysis conducted on the 46 food categories which compose the typical Italian diet. Overnutrition in the South-Islands regions of Italy exerts the largest impact (31.6%), followed by the North-West (26.6%), the Centre (22.2%), and the North-East (19.1%).
Interdisk spacing effect on resonant properties of Ge disk lattices on Si substrates
Authors: Shklyaev A. A. , Utkin D. E. , Tsarev A. V. , Kuznetsov S. A. , Anikin K. V. , Latyshev A. V.
Published: May 2022

The light reflection properties of Ge disk lattices on Si substrates are studied as a function of the disk height and the gap width between disks. The interdisk spacing effect is observed even at such large gap widths as 500 nm. The gap width decrease leads to the appearance of the reflection minimum in the short wavelength region relative to one originated from the magnetic and electric dipole resonances in individual Ge disks, thereby essentially widening the antireflection properties. This minimum becomes significantly deeper at small gap widths. The observed behavior is associated with the features of the resonant fields around closely spaced disks according to numerical simulation data. The result shows the importance of using structures with geometrical parameters providing the short-wavelength minimum. This can essentially enhance their other resonant properties, which are widely used for applications, in particular, based on collective lattice resonances.
Changing surface ocean circulation caused the local demise of echinoid Scaphechinus mirabilis in Taiwan during the Pleistocene–Holocene transition
Authors: Ho Sze Ling , Wang Jia-Kang , Lin Yu-Jou , Lin Ching-Ren , Lee Chen-Wei , Hsu Chia-Hsin , Chang Lo-Yu , Wu To-Hsiang , Tseng Chien-Chia , Wu Hsiao-Jou , John Cédric M. , Oji Tatsuo , Liu Tsung-Kwei , Chen Wen-Shan , Li Peter , Fang Jiann-Neng , Lin Jih-Pai
Published: May 2022

Abundant fossil specimens of Scaphechinus mirabilis, now occurring mostly in temperate waters, have been found in the Toukoshan Formation (Pleistocene) in Miaoli County, Taiwan. Environmental changes leading to its extirpation (local extinction) have thus far been elusive. Here, we reconstruct past environmental and oceanic conditions off northwest Taiwan by analyzing clumped isotopes, as well as stable oxygen isotopes, of well-preserved fossil echinoid tests collected from the Toukoshan Formation. Radiocarbon dates suggest that these samples are from Marine Isotope Stage 3 (MIS 3). Paleotemperature estimates based on clumped isotopes indicate that fossil echinoids were living in oceanic conditions that range from 9 to 14 °C on average, comparable with the estimate derived for a modern sample from Mutsu Bay, Japan. Notably, this temperature range is ~ 10 °C colder than today’s conditions off northwest Taiwan. The substantially lower temperatures during ~ 30 ka (MIS 3) compared to the modern conditions might be due to the rerouting of surface currents off northwest Taiwan when the sea level was ~ 60 m lower than today, in addition to the cooling caused by a lower atmospheric CO2 level during the Last Glacial Period. Colder waters brought here by the China Coastal Current (CCC) and the existence of shallow subtidal zones termed “Miaoli Bay” (mainly located in the present-day Miaoli county) during MIS 3 plausibly sustained generations of S. mirabilis, yielding tens of thousands of fossil specimens in the well-preserved fossil beds. The likely extirpation driver is the drastic change from a temperate climate to much warmer conditions in the shallow sea during the Pleistocene–Holocene transition.
Micro-computed tomography assessment of bone structure in aging mice
Authors: Shim Junbo , Iwaya Chihiro , Ambrose Catherine G. , Suzuki Akiko , Iwata Junichi
Published: May 2022

High-resolution computed tomography (CT) is widely used to assess bone structure under physiological and pathological conditions. Although the analytic protocols and parameters for micro-CT (μCT) analyses in mice are standardized for long bones, vertebrae, and the palms in aging mice, they have not yet been established for craniofacial bones. In this study, we conducted a morphometric assessment of craniofacial bones, in comparison with long bones, in aging mice. Although age-related changes were observed in the microarchitecture of the femur, tibia, vertebra, and basisphenoid bone, and were more pronounced in females than in males, the microarchitecture of both the interparietal bone and body of the mandible, which develop by intramembranous ossification, was less affected by age and sex. By contrast, the condyle of the mandible was more affected by aging in males compared to females. Taken together, our results indicate that mouse craniofacial bones are uniquely affected by age and sex.
Urban seismic resilience mapping: a transportation network in Istanbul, Turkey
Authors: Byun Ji-Eun , D’Ayala Dina
Published: May 2022

When a seismic event occurs, transportation networks play a critical role in undertaking emergency activities such as evacuation and relief supply. Accordingly, to secure their functionality, it is essential to accurately assess their resilience. In particular, this study performs a rigorous probabilistic analysis on the seismic resilience of a transportation network in Istanbul, Turkey. The analysis accuracy is enhanced by considering, along with the structural damage of roadways, the additional disruption mode of network performance caused by the debris falling from damaged objects in their vicinity. Moreover, we obtain the results as a map of resilience measure, which enables us to investigate the disruption inequality across the study area and identify critical factors that govern the system resilience. To enable such sophisticated probabilistic analysis, a Bayesian network (BN) model is developed that involves various types of information from the hazard process to the performance of structures and systems. Then, the BN is quantified by identifying and compiling a comprehensive list of datasets. Thereby, this study analyses large-scale systems involving thousands of structures, while providing general probabilistic models and data schema that can be employed for other transportation networks.
Normal and tangential forces combine to convey contact pressure during dynamic tactile stimulation
Authors: Gueorguiev David , Lambert Julien , Thonnard Jean-Louis , Kuchenbecker Katherine J.
Published: May 2022

Humans need to accurately process the contact forces that arise as they perform everyday haptic interactions such as sliding the fingers along a surface to feel for bumps, sticky regions, or other irregularities. Several different mechanisms are possible for how the forces on the skin could be represented and integrated in such interactions. In this study, we used a force-controlled robotic platform and simultaneous ultrasonic modulation of the finger-surface friction to independently manipulate the normal and tangential forces during passive haptic stimulation by a flat surface. To assess whether the contact pressure on their finger had briefly increased or decreased during individual trials in this broad stimulus set, participants did not rely solely on either the normal force or the tangential force. Instead, they integrated tactile cues induced by both components. Support-vector-machine analysis classified physical trial data with up to 75% accuracy and suggested a linear perceptual mechanism. In addition, the change in the amplitude of the force vector predicted participants’ responses better than the change of the coefficient of dynamic friction, suggesting that intensive tactile cues are meaningful in this task. These results provide novel insights about how normal and tangential forces shape the perception of tactile contact.
Signal-in-space range error and positioning accuracy of BDS-3
Authors: Liu Weiping , Jiao Bo , Hao Jinming , Lv Zhiwei , Xie Jiantao , Liu Jing
Published: May 2022

Being the first mixed-constellation global navigation system, the global BeiDou navigation system (BDS-3) designs new signals, the service performance of which has attracted extensive attention. In the present study, the Signal-in-space range error (SISRE) computation method for different types of navigation satellites was presented. The differential code bias (DCB) correction method for BDS-3 new signals was deduced. Based on these, analysis and evaluation were done by adopting the actual measured data after the official launching of BDS-3. The results showed that BDS-3 performed better than the regional navigation satellite system (BDS-2) in terms of SISRE. Specifically, the SISRE of the BDS-3 medium earth orbit (MEO) satellites reached 0.52 m, slightly inferior compared to 0.4 m from Galileo, marginally better than 0.59 m from GPS, and significantly better than 2.33 m from GLONASS. The BDS-3 inclined geostationary orbit (IGSO) satellites achieved the SISRE of 0.90 m, on par with that (0.92 m) of the QZSS IGSO satellites. However, the average SISRE of BDS-3 geostationary earth orbit (GEO) satellites was 1.15 m, which was marginally inferior to that of the QZSS GEO satellite (0.91 m). In terms of positioning accuracy, the new signals B1C and B2a are considered together with the transition signals B1I and B3I. The overall three-dimensional single-frequency standard point positioning (SPP) accuracy of BDS-3 B1C, B2a, B1I, and B3I gained an accuracy level better than 5 m. Moreover, the B1I signal exhibited the best positioning accuracy in the Asian-Pacific region, while the B1C signal set forth the best positioning accuracy in the other regions. Owing to the advantage in signal frequency, the dual-frequency SPP accuracy of B1C + B2a surpassed that of the transitional signal of B1I + B3I. Since there are more visible satellites in Asia–Pacific, the positioning accuracy of BDS-3 was moderately superior to that of GPS. The precise point positioning (PPP) accuracy of BDS-3 B1C + B2a or B1I + B3I converged to the order of centimeters, marginally inferior to that of the GPS L1 + L2. However, these three combinations had a similar convergence time of approximately 30 min.
Cell-controlled dynamic surfaces for skeletal stem cell growth and differentiation
Authors: Anderson Hilary J. , Sahoo Jugal Kishore , Wells Julia , van Nuffel Sebastiaan , Dhowre Hala S. , Oreffo Richard O. C. , Zelzer Mischa , Ulijn Rein V. , Dalby Matthew J.
Published: May 2022

Skeletal stem cells (SSCs, or mesenchymal stromal cells typically referred to as mesenchymal stem cells from the bone marrow) are a dynamic progenitor population that can enter quiescence, self-renew or differentiate depending on regenerative demand and cues from their niche environment. However, ex vivo, in culture, they are grown typically on hard polystyrene surfaces, and this leads to rapid loss of the SSC phenotype. While materials are being developed that can control SSC growth and differentiation, very few examples of dynamic interfaces that reflect the plastic nature of the stem cells have, to date, been developed. Achieving such interfaces is challenging because of competing needs: growing SSCs require lower cell adhesion and intracellular tension while differentiation to, for example, bone-forming osteoblasts requires increased adhesion and intracellular tension. We previously reported a dynamic interface where the cell adhesion tripeptide arginine-glycine-aspartic acid (RGD) was presented to the cells upon activation by user-added elastase that cleaved a bulky blocking group hiding RGD from the cells. This allowed for a growth phase while the blocking group was in place and the cells could only form smaller adhesions, followed by an osteoblast differentiation phase that was induced after elastase was added which triggered exposure of RGD and subsequent cell adhesion and contraction. Here, we aimed to develop an autonomous system where the surface is activated according to the need of the cell by using matrix metalloprotease (MMP) cleavable peptide sequences to remove the blocking group with the hypothesis that the SSCs would produce higher levels of MMP as the cells reached confluence. The current studies demonstrate that SSCs produce active MMP-2 that can cleave functional groups on a surface. We also demonstrate that SSCs can grow on the uncleaved surface and, with time, produce osteogenic marker proteins on the MMP-responsive surface. These studies demonstrate the concept for cell-controlled surfaces that can modulate adhesion and phenotype with significant implications for stem cell phenotype modulation.
Response-related sensorimotor rhythms under scopolamine and MK-801 exposures in the touchscreen visual discrimination test in rats
Authors: Kostyalik Diána , Kelemen Kristóf , Lendvai Balázs , Hernádi István , Román Viktor , Lévay György
Published: May 2022

The human mu rhythm has been suggested to represent an important function in information processing. Rodent homologue rhythms have been assumed though no study has investigated them from the cognitive aspect yet. As voluntary goal-directed movements induce the desynchronization of mu rhythm, we aimed at exploring whether the response-related brain activity during the touchscreen visual discrimination (VD) task is suitable to detect sensorimotor rhythms and their change under cognitive impairment. Different doses of scopolamine or MK-801 were injected subcutaneously to rats, and epidural electroencephalogram (EEG) was recorded during task performance. Arciform ~ 10 Hz oscillations appeared during visual processing, then two characteristic alpha/beta desynchronization-resynchronization patterns emerged mainly above the sensorimotor areas, serving presumably different motor functions. Beyond causing cognitive impairment, both drugs supressed the touch-related upper alpha (10–15 Hz) reactivity for desynchronization. Reaction time predominantly correlated positively with movement-related alpha and beta power both in normal and impaired conditions. These results support the existence of a mu homologue rodent rhythm whose upper alpha component appeared to be modulated by cholinergic and glutamatergic mechanisms and its power change might indicate a potential EEG correlate of processing speed. The VD task can be utilized for the investigation of sensorimotor rhythms in rats.
CNN-based flow control device modelling on aerodynamic airfoils
Authors: Portal-Porras Koldo , Fernandez-Gamiz Unai , Zulueta Ekaitz , Ballesteros-Coll Alejandro , Zulueta Asier
Published: May 2022

Wind energy has become an important source of electricity generation, with the aim of achieving a cleaner and more sustainable energy model. However, wind turbine performance improvement is required to compete with conventional energy resources. To achieve this improvement, flow control devices are implemented on airfoils. Computational fluid dynamics (CFD) simulations are the most popular method for analyzing this kind of devices, but in recent years, with the growth of Artificial Intelligence, predicting flow characteristics using neural networks is becoming increasingly popular. In this work, 158 different CFD simulations of a DU91W(2)250 airfoil are conducted, with two different flow control devices, rotating microtabs and Gurney flaps, added on its Trailing Edge (TE). These flow control devices are implemented by using the cell-set meshing technique. These simulations are used to train and test a Convolutional Neural Network (CNN) for velocity and pressure field prediction and another CNN for aerodynamic coefficient prediction. The results show that the proposed CNN for field prediction is able to accurately predict the main characteristics of the flow around the flow control device, showing very slight errors. Regarding the aerodynamic coefficients, the proposed CNN is also capable to predict them reliably, being able to properly predict both the trend and the values. In comparison with CFD simulations, the use of the CNNs reduces the computational time in four orders of magnitude.
Formaldehyde exposure induces differentiation of regulatory T cells via the NFAT-mediated T cell receptor signalling pathway in Yucatan minipigs
Authors: Park Jeongsik , Kang Goo-Hwa , Kim Youngkyu , Lee Ju Young , Song Jeong Ah , Hwang Jeong Ho
Published: May 2022

The use of minipigs (Sus scrofa) as a platform for toxicological and pharmacological research is well established. In the present study, we investigated the effect of formaldehyde (FA) exposure on helper T cell-mediated splenic immune responses in Yucatan minipigs. The minipigs were exposed to different inhaled concentrations of FA (0, 2.16, 4.62, or 10.48 mg/m3) for a period of 2 weeks. Immune responses elicited by exposure to FA were determined by assessing physiological parameters, mRNA expression, and cytokine production. Additionally, the distribution of helper T cells and regulatory T (Treg) cells and expression of NFAT families, which are well-known T cell receptor signalling proteins associated with regulatory T cell development, were evaluated. Exposure to FA suppressed the expression of genes associated with Th1 and Th2 cells in minipigs in a concentration-dependent manner. The subsequent production of cytokines also declined post-FA exposure. Furthermore, exposure to FA induced the differentiation of CD4+ Foxp3+ Treg cells with divergent expression levels of NFAT1 and NFAT2. These results indicated that exposure to FA increased the Treg cell population via the NFAT-mediated T cell receptor signalling pathway, leading to suppression of effector T cell activity with a decline in T cell-related cytokine production.
Reconstructing SNP allele and genotype frequencies from GWAS summary statistics
Authors: Yang Zhiyu , Paschou Peristera , Drineas Petros
Published: May 2022

The emergence of genome-wide association studies (GWAS) has led to the creation of large repositories of human genetic variation, creating enormous opportunities for genetic research and worldwide collaboration. Methods that are based on GWAS summary statistics seek to leverage such records, overcoming barriers that often exist in individual-level data access while also offering significant computational savings. Such summary-statistics-based applications include GWAS meta-analysis, with and without sample overlap, and case-case GWAS. We compare performance of leading methods for summary-statistics-based genomic analysis and also introduce a novel framework that can unify usual summary-statistics-based implementations via the reconstruction of allelic and genotypic frequencies and counts (ReACt). First, we evaluate ASSET, METAL, and ReACt using both synthetic and real data for GWAS meta-analysis (with and without sample overlap) and find that, while all three methods are comparable in terms of power and error control, ReACt and METAL are faster than ASSET by a factor of at least hundred. We then proceed to evaluate performance of ReACt vs an existing method for case-case GWAS and show comparable performance, with ReACt requiring minimal underlying assumptions and being more user-friendly. Finally, ReACt allows us to evaluate, for the first time, an implementation for calculating polygenic risk score (PRS) for groups of cases and controls based on summary statistics. Our work demonstrates the power of GWAS summary-statistics-based methodologies and the proposed novel method provides a unifying framework and allows further extension of possibilities for researchers seeking to understand the genetics of complex disease.
Heat shock protein Grp78/BiP/HspA5 binds directly to TDP-43 and mitigates toxicity associated with disease pathology
Authors: François-Moutal Liberty , Scott David Donald , Ambrose Andrew J. , Zerio Christopher J. , Rodriguez-Sanchez Marina , Dissanayake Kumara , May Danielle G. , Carlson Jacob M. , Barbieri Edward , Moutal Aubin , Roux Kyle J. , Shorter James , Khanna Rajesh , Barmada Sami J. , McGurk Leeanne , Khanna May
Published: May 2022

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure or effective treatment in which TAR DNA Binding Protein of 43 kDa (TDP-43) abnormally accumulates into misfolded protein aggregates in affected neurons. It is widely accepted that protein misfolding and aggregation promotes proteotoxic stress. The molecular chaperones are a primary line of defense against proteotoxic stress, and there has been long-standing interest in understanding the relationship between chaperones and aggregated protein in ALS. Of particular interest are the heat shock protein of 70 kDa (Hsp70) family of chaperones. However, defining which of the 13 human Hsp70 isoforms is critical for ALS has presented many challenges. To gain insight into the specific Hsp70 that modulates TDP-43, we investigated the relationship between TDP-43 and the Hsp70s using proximity-dependent biotin identification (BioID) and discovered several Hsp70 isoforms associated with TDP-43 in the nucleus, raising the possibility of an interaction with native TDP-43. We further found that HspA5 bound specifically to the RNA-binding domain of TDP-43 using recombinantly expressed proteins. Moreover, in a Drosophila strain that mimics ALS upon TDP-43 expression, the mRNA levels of the HspA5 homologue (Hsc70.3) were significantly increased. Similarly we observed upregulation of HspA5 in prefrontal cortex neurons from human ALS patients. Finally, overexpression of HspA5 in Drosophila rescued TDP-43-induced toxicity, suggesting that upregulation of HspA5 may have a compensatory role in ALS pathobiology.
Cytotoxic and antimicrobial activities of two new sesquiterpenoids from red sea brittle star Ophiocoma dentata
Authors: El Feky Shaymaa E. , Abd El Hafez Mohamed S. M. , Abd El Moneim Nadia A. , Ibrahim Hassan A. H. , Okbah Mohamed A. , Ata Athar , El Sedfy Amel S. , Hussein Ahmed
Published: May 2022

Bioactive compounds were extracted from a locally available brittle star; Ophiocoma dentata, collected from the Red Sea, Egypt. Two new sesquiterpenoids; 8, 11-epoxy-9(15)-himachaladiene-4-ol (O8-ophiocomane) and, 11-epoxy-9(15)-himachaladiene-4-ol (O7-ophiocomane) were isolated and characterized using appropriate techniques. Structure elucidation was estimated via 1D NMR, 2D NMR, FT-IR and mass spectroscopy analyses. The isolated compounds were tested for cytotoxic, antibacterial and antifungal activities. Pure compounds showed a dose dependent reduction in MCF-7 cells viability with LC50 of 103.5 and 59.5 μg/ml for compounds 1 and 2 respectively compared to the chemotherapeutic drug cisplatin (47.4 µg/ml). In vivo experiments showed that O. dentate extract significantly reduced tumor progression and improved hematological parameters and liver functions of tumor-bearing mice when administered either before or after tumor cells’ injection. The most remarkable antimicrobial effects of O. dentate crude extract were against Staphylococcus aureus, Vibrio damsela and Pseudomonasaeruginosa while the pure compounds showed activity against P. aeruginosa alone. Neither the crude extract nor the pure compounds have shown activity against Aeromonas hydrophila. These results indicates that O. dentata extract and newly isolated compounds have shown a promising cytotoxic, antiproliferative and antimicrobial activities that might be useful for pharmaceutical applications.
Preclinical trial of noncontact anthropometric measurement using IR-UWB radar
Authors: Kim Jinsup , Lee Won Hyuk , Kim Seung Hyun , Na Jae Yoon , Lim Young-Hyo , Cho Seok Hyun , Cho Sung Ho , Park Hyun-Kyung
Published: May 2022

Anthropometric profiles are important indices for assessing medical conditions, including malnutrition, obesity, and growth disorders. Noncontact methods for estimating those parameters could have considerable value in many practical situations, such as the assessment of young, uncooperative infants or children and the prevention of infectious disease transmission. The purpose of this study was to investigate the feasibility of obtaining noncontact anthropometric measurements using the impulse-radio ultrawideband (IR-UWB) radar sensor technique. A total of 45 healthy adults were enrolled, and a convolutional neural network (CNN) algorithm was implemented to analyze data extracted from IR-UWB radar. The differences (root-mean-square error, RMSE) between values from the radar and bioelectrical impedance analysis (BIA) as a reference in the measurement of height, weight, and body mass index (BMI) were 2.78, 5.31, and 2.25, respectively; predicted data from the radar highly agreed with those from the BIA. The intraclass correlation coefficients (ICCs) were 0.93, 0.94, and 0.83. In conclusion, IR-UWB radar can provide accurate estimates of anthropometric parameters in a noncontact manner; this study is the first to support the radar sensor as an applicable method in clinical situations.
Efficient world-line-based quantum Monte Carlo method without Hubbard–Stratonovich transformation
Authors: Wang J. , Pan W. , Sun D. Y.
Published: May 2022

By precisely writing down the matrix element of the local Boltzmann operator ($${\mathrm{e}}^{-\tau h}$$

e

-
τ
h

, where $$h$$
h
is the Hermitian conjugate pairs of off-diagonal operators), we have proposed a new path integral formulation for quantum field theory and developed a corresponding Monte Carlo algorithm. With the current formula, the Hubbard–Stratonovich transformation is not necessary, accordingly the determinant calculation is not needed, which can improve the computational efficiency. The results show that, the simulation time has the square-law scaling with system sizes, which is comparable with the usual first-principles calculations. The current formula also improves the accuracy of the Suzuki–Trotter decomposition. As an example, we have studied the one-dimensional half-filled Hubbard model at finite temperature. The obtained results are in excellent agreement with the known solutions. The new formula and Monte Carlo algorithm could be applied to various studies in future.
Nanoporous and nano thickness film-forming bioactive composition for biomedical applications
Authors: Chevala Naga Thirumalesh , Kumar Lalit , Veetilvalappil Vimal , Mathew Aranjani Jesil , Paonam Bemma , Mohan Ganesh , Shastry Shamee , Balasubramanian Krishnan , Rao C. Mallikarjuna
Published: May 2022

Unmanageable bleeding is one of the significant causes of mortality. Attaining rapid hemostasis ensures subject survivability as a first aid during combats, road accidents, surgeries that reduce mortality. Nanoporous fibers reinforced composite scaffold (NFRCS) developed by a simple hemostatic film-forming composition (HFFC) (as a continuous phase) can trigger and intensify hemostasis. NFRCS developed was based on the dragonfly wing structure's structural design. Dragonfly wing structure consists of cross-veins and longitudinal wing veins inter-connected with wing membrane to maintain the microstructural integrity. The HFFC uniformly surface coats the fibers with nano thickness film and interconnects the randomly distributed cotton gauge (Ct) (dispersed phase), resulting in the formation of a nanoporous structure. Integrating continuous and dispersed phases reduce the product cost by ten times that of marketed products. The modified NFRCS (tampon or wrist band) can be used for various biomedical applications. The in vivo studies conclude that the developed Cp NFRCS triggers and intensifies the coagulation process at the application site. The NFRCS could regulate the microenvironment and act at the cellular level due to its nanoporous structure, which resulted in better wound healing in the excision wound model.
Study on dynamic safety distance of multi-storey buildings on the top of loess slope
Authors: Wang Lili , Li Ning , Wang Ping
Published: May 2022

In view of the frequent occurrence of strong earthquakes and the actual characteristics of buildings built on the top of slopes in the loess region of Western China, the dynamic response and stability law of loess slope under the building load on the top of the slope are discussed by using the three-dimensional finite element numerical calculation method. Taking the slope safety factor, acceleration amplification coefficient, building permanent displacement and slope sliding range as evaluation indexes, the dynamic safety of buildings on the top of the slope under earthquake is analyzed, and the recommended value of dynamic safety distance between top building and slope shoulder is put forward. The results show that: firstly, affected by the amplification effect of slope elevation, the dynamic response of buildings on the top of slope is stronger than that of buildings under slope. At the same time, affected by the amplification effect of the free surface of the slope, the dynamic response amplitude of the building is negatively correlated with the distance from the slope shoulder. Secondly, the horizontal acceleration ratio between the top building and the under building is the largest at the height of 3–6 m, indicating that the multi-storey building with pile raft foundation is most prone to damage at this height. Thirdly, the dynamic safety distance of multi-storey buildings with pile raft foundation located on the top of loess slope with slope height H ≤ 30 m and slope gradient 25° ≤ α ≤ 70° can be 24 m.