bluuebunny/crossref_metadata_2025 huggingface dataset:
The influence on optimal structural designs
of the modelling processes and design
concepts
Authors: Anastasiadis P. T. , Morris A. J.
Published: February 2023

The paper examines the influence on optimal structural
designs of changing the finite element selection,
the structural design criteria and the design
concepts for an unmanned air-vehicle wing. Thus,
single and twin-spar designs are considered with a
number of composite design configurations. The
results indicate that some of the design criteria
have little influence on the optimal designs whilst
finite element selection can be significant.
On the effect of a swept-wing–plate
junction flow on the lift and drag
Authors: Bernstein L. , Hamid S.
Published: February 2023

Measurements have been made of the surface pressure
distributions in the region of the junction between
an untapered wing, of NACA 0015 section swept back
at 20°, and a flat plate on which a turbulent
boundary layer had developed, for several values of
wing incidence. It is shown that the section lift
coefficient of the wing diminishes, while the
pressure drag coefficient increases, as the junction
is approached. Oil-flow visualisations on the plate
surface show the passage of the horseshoe-like
vortex which forms when the retarded boundary layer
flow separates as it approaches the leading-edge of
the junction. Kinks in the isobars on the plate
correlate with the trailing “legs” of this vortex.
The surface flow visualisations also show that the
turbulence in the junction region spreads onto the
wing from the leading edge at an angle of about
10°.

A rotatable X-wire anemometer was used to make
measurements of the mean velocity field and of five
components of the Reynolds stress tensor, in the
wake of the junction, with the wing at incidences of
0° and 9°. Log-law (Clauser) plots were used with
the profiles Ū(Y) of longitudinal
velocity to estimate the skin friction coefficient
on the plate, though adjustments of the zero for
Y were necessary to obtain a
sensible fit. These corrections were often larger
than can be readily explained, but the skin-friction
values are consistent with the corresponding,
measured velocity correlation, . The Reynolds stresses in
the wake region clearly show that the horseshoe-like
vortex legs persist beyond the trailing-edge of the
wing, the turbulence intensity being larger on the
suction side for the wing at incidence.

Average values of the skin-friction coefficient on the
plate in the junction region are little different
from those away from the junction. No corresponding
information is available for the skin-friction on
the wing, but if this is likewise unaffected by the
junction, then the total drag of the junction region
will be greater than the sum of those of the
isolated parts, simply because of the increase in
pressure drag.
An overview of the Boeing 777 high lift
aerodynamic design
Authors: B. N. Nield
Published: February 2023

The process of designing the Boeing 777 high lift
system is described. Particular attention is given
to design constraints and examples are given of the
trade studies completed. The theoretical design
tools and experimental test program are described. A
survey of the high lift elements is presented and
flight test results are compared with
predictions.
Dynamic stall vortex convection: thoughts
on compressibility effects
Authors: Green R. B. , Galbraith R. A. McD.
Published: February 2023

This paper considers the convection of the dynamic
stall vortex. A brief discussion of existing data is
given. A comparison of two sets of data from
different experimental facilities is then presented,
and it is indicated that an important anomaly exists
concerning the behaviour of the dynamic stall
vortex. It emerges that freestream Mach number is
the only parameter that can account for the observed
differences. The importance of this parameter is
then discussed in the context of vorticity flux from
the aerofoil surface.
Comparison of numerical and experimental
drag measurement in hypervelocity
flow
Authors: Smith A. L. , Johnston I. A. , Austin K. J.
Published: February 2023

In planning interplanetary missions which involve an
aerobraking manoeuvre, it is necessary to make
accurate predictions of the aerodynamic drag acting
on a vehicle during its descent. Of interest to the
authors is the Nasa initiative for exploration of
Mars and its atmosphere. The Mars Pathfinder is a
probe that is expected to enter the Martian
atmosphere at a relative velocity of approximately
7.6 kms-1;. The forebody of this vehicle
is based on a 70° blunted cone and is typical of
aerobraking designs.

In this note, a comparison is made between experimental
and numerical techniques for predicting drag in
hypervelocity flow. Three different models were
examined in this study: a 30° sharp cone; an Apollo
heat shield; and a Viking heat shield. A relatively
simple analytical result for the drag on a cone
provides a convenient reference for both the
experimental and numerical results. The two heat
shields are typical of those used for interplanetary
exploration, such as the Mars Pathfinder. Our aim is
to give an example of how computational fluid
dynamics can be used in conjunction with experiments
to obtain information about the hypervelocity flow
about re-entry vehicles.
Space: towards the next
millennium
Authors: Williamson M.
Published: February 2023

The space industry of the late 20th century is not
simply a subset of the aerospace industry: it is a
producer, an employer and a wealth creator in its
own right. This paper reviews the current state of
the art in space technology by analysing the
development of an industry which produces both a
wide variety of spacecraft and the launch vehicles
which deliver them to orbit. In doing so, it
considers the application of spacecraft for
communications, navigation. Earth observation and
science, as well as their application to manned
space flight.

By considering some of the problems that need to be
solved in order to develop the field beyond its
current state, the paper then looks forward to the
developments in these areas expected in the 21st
century. The interrelated development of
international co-operation — as opposed to political
competition — and the rise of space
commercialisation is considered throughout.
Instrumente und Arbeitshilfen bei der Einschätzung der Arbeitsfähigkeit
Authors: Klipstein Andreas , Trippolini Maurizio
Published: February 2023

Zusammenfassung. Bei krankheits- und unfallbedingten Arbeitsausfällen kommt dem behandelnden Arzt/der behandelnden Ärztin die Aufgabe zu, den Zusammenhang zwischen einer Arbeitsabsenz (oder allenfalls einer reduzierten Leistung) und einer Gesundheitsstörung (Krankheit oder Unfall) zu bestätigen und in der Folge ein Arbeitsunfähigkeitszeugnis auszustellen. Die Atteste haben den rechtlichen Status einer Urkunde und haben entsprechend gewissen gesetzlichen Voraussetzungen zu genügen. Dieser Artikel stellt für diese wichtige ärztliche Aufgabe geeignete Instrumente und Arbeitshilfen vor, von denen die meisten online verfügbar sind.
Allgemeinärztliche Fertigkeiten in der polydisziplinären Begutachtung
Authors: Schaad Heinz J.
Published: February 2023

Zusammenfassung. In der polydisziplinären Begutachtung spielt der Fallführer eine zentrale Rolle. Bis anhin hat in jedem polydisziplinären Gutachten der Invalidenversicherung ein Facharzt für «Allgemeine Innere Medizin» mitgewirkt. Medizinische Generalisten sind aufgrund ihrer alltäglichen klinischen Tätigkeit prädestiniert, die Rolle des Fallführers auszufüllen. Ein eigenes Modul «Fallführung» in der gutachterlichen Weiterbildung könnte die heterogenen Facetten der Fallführung vereinheitlichen, spezifische Zuständigkeiten im polydisziplinären Prozess vermitteln und das Aufgabenprofil schärfen. Dies würde den Fallführer befähigen, die gesetzlichen Erwartungen an die Qualitätssicherung in der polydisziplinären Begutachtung einheitlich umzusetzen.
MAS/DAS/CAS VMed
Authors: Bollag Yvonne , Lüssen Antje Welge
Published: February 2023

Zusammenfassung. Das facettenreiche, interdisziplinär aufgebaute akademische Nachdiplomstudium MAS Versicherungsmedizin an der Universität Basel bietet auf drei Levels – Master (MAS), Diplom (DAS), Zertifikat (CAS) – die aktuell umfassendste Weiterqualifizierung in dieser Fachrichtung. Individuelle Lernformate ermöglichen eine optimale Abstimmung mit individuellen beruflichen Bedürfnissen. Die Lehrinhalte umfassen neben spezifischen versicherungsmedizinischen Themen auch wichtige Krankheitsbilder, evidenzbasierte Versicherungsmedizin und Public Health wie gesundheitsökonomische, ethische und rechtliche Themen.
Submesoscale Effects on Changes to Export Production Under Global Warming
Authors: Brett Genevieve Jay , Whitt Daniel B , Long Matthew C , Bryan Frank O. , Feloy Kate , Richards Kelvin J.
Published: February 2023

We examine the effects of the submesoscale in mediating the response to projected warming of phytoplankton new production and export using idealized biogeochemical tracers in a high‐resolution regional model of the Porcupine Abyssal Plain region of the North Atlantic. We quantify submesoscale effects by comparing our control run to an integration in which submesoscale motions have been suppressed using increased viscosity. Annual new production is slightly reduced by submesoscale motions in a climate representative of the early 21st‐century and slightly increased by submesoscale motions in a climate representative of the late 21st‐century. The warmer climate at the end of the 21st century reduces resolved submesoscale activity by a factor of 2–3. Resolving the submesoscale, however, does not strongly impact the projected reduction in annual production under representative warming. Organic carbon export from the surface ocean includes both direct sinking of detritus (the biological gravitational pump) and advective transport mediated pathways; the sinking component is larger than advectively mediated vertical transport by up to an order of magnitude across a wide range of imposed sinking rates. The submesoscales are responsible for most of the advective carbon export, however, which is thus largely reduced in a warmer climate. In summary, our results demonstrate that resolving more of the submesoscale has a modest effect on present‐day new production, a small effect on simulated reductions in new production under global warming, and a large effect on advectively mediated export fluxes.
Upper Crustal Structure of Superfast‐Spread Oceanic Crust Exposed at the Pito Deep Rift: Implications for Seafloor Spreading
Authors: Karson J. A. , Chutas L. A. , Hayman N. W. , Hey R. N. , Horst A. J. , Hurst S. D. , Klein E. M. , Naar D. F. , Varga R. J.
Published: February 2023

A tectonic window into the upper 2,000 m of oceanic crust generated at the superfast spreading (∼142 mm/yr) southern East Pacific Rise exposes a continuous layered structure of basaltic lavas and sheeted dikes over gabbroic rocks. This relatively simple structure is in accord with expectations for crustal accretion at a very fast spreading rate and high magma budget where magmatic construction keeps pace with plate separation. Detailed observations show that basaltic lava flows dip progressively more steeply inward (toward the spreading axis where they were erupted). Underlying sheeted dikes are faulted and tectonically rotated to dip steeply outward. These structures are interpreted in terms of subsidence beneath the axis of the southern East Pacific Rise during crustal construction that allowed the lava unit to thicken to >400 m without creating comparable relief at the spreading center. Transitional units above and below the sheeted dike complex show that the thickness of upper crustal rock units is modified by tectonic and intrusive processes during accretion. The crustal structure shows that even approaching the superfast spreading end‐member of seafloor spreading, crustal accretion involves dramatic tectonic processes that are not obvious from the surface geology of spreading centers.
Finding Causal Gateways of Precipitation Over the Contiguous United States
Authors: Yang Xueli , Wang Zhi‐Hua , Wang Chenghao , Lai Ying‐Cheng
Published: February 2023

Identifying regions that mediate regional propagation of atmospheric perturbations is important to assessing the susceptibility and resilience of complex hydroclimate systems. Detecting the regional gateways through causal inference, can help unravel the interplay of physical processes and inform projections of future changes. In this study, we characterize the causal interactions among nine climate regions in the contiguous United States using long‐term (1901–2018) precipitation data. The constructed causal networks reveal the cross‐regional propagation of precipitation perturbations. Results show that the Ohio Valley region acts as an atmospheric gateway for precipitation and moisture transport in the U.S., which is largely regulated by the regional convective uplift. The findings have implications for improving predicative capacity of hydroclimate modeling of regional precipitation.
On Current Sheets and Associated Density Spikes in Titan’s Ionosphere as Seen From Cassini
Authors: Kim Konstantin , Edberg Niklas J. T. , Shebanits Oleg , Wahlund Jan‐Erik , Vigren Erik , Bertucci Cesar
Published: February 2023

The Cassini spacecraft made in‐situ measurements of Titan's plasma environment during 126 close encounters between 2004 and 2017. Here we report on observations from the Radio and Plasma Waves System/Langmuir probe instrument (RPWS/LP) from which we have observed, primarily on the outbound leg, a localized increase of the electron density by up to 150 cm−3 with respect to the background. This feature, appearing as an electron density spike in the data, is found during 28 of the 126 flybys. The data from RPWS/LP, the electron spectrometer from the Cassini Plasma Spectrometer package , and the magnetometer is used to calculate electron densities and magnetic field characteristics. The location of these structures around Titan with respect to the nominal corotation direction and the sun direction is investigated. We find that the electron density spikes are primarily observed on the dayside and ramside of Titan. We also observe magnetic field signatures that could suggest the presence of current sheets in most cases. The density spikes are extended along the trajectory of the spacecraft with the horizontal scale of ∼537 ± 160 km and vertical scale ∼399 ± 163 km. We suggest that the density spikes are formed as a result of the current sheet formation.
Extreme Copper Isotope Fractionation Driven by Redox Oscillation During Gleysols Weathering in Mun River Basin, Northeast Thailand
Authors: Zheng Xiaodi , Han Guilin , Zhang Qian , Liang Bin , Liu Man , Yu Changxun , Liu Linan , Zhao Ye , Song Zhaoliang
Published: February 2023

Copper (Cu) isotopes are utilized to track Cu geochemical cycling in weathered gleysols of tropical zones. A significant isotope fractionation of Cu in these soils is primarily redox‐controlled; however, it is rarely reported how the frequency of redox fluctuations affects the soil Cu isotope signature. This study investigated the variations of Cu content and isotope fractionation in two low‐humic gleysol profiles (S1 and S2) from a dry tropical savanna zone. Owing to redox oscillation during weathering, δ65Cu values in profile S2 showed a stronger positive correlation with the mafic index of alteration of reducing environment than S1, and isotopically light Cu is more retained in the Zone II of profile S2 than S1. As the frequency of redox fluctuation increased, the retained stable Cu(I) species and light Cu isotopes increased in the residual soils through re‐adsorption or re‐precipitation by iron oxyhydroxide (i.e., ferrihydrite). Importantly, an Mn‐enriched zone was formed after reduction events in profile S2, and found to be enriched in light Cu isotopes. The heavier Cu fraction might be lost by adsorption on Fe oxyhydroxides in the Mn‐rich zone, while the relatively light Cu might be retained through adsorption on Mn oxyhydroxides. Additionally, a significant Soil Organic Carbon (SOC) contribution to Cu was found due to the high δ65Cu‐SOC correlation (R2 = 0.80) in S1 (depth <1 m). Therefore, our study shows that the Cu isotope signature can respond to redox changes in the terrestrial ecosystem, and these Cu isotope signatures may have significant implications for assessing soil ecological vulnerability under future climate change scenarios.
Surface and Crustal Response to Deep Subduction Dynamics: Insights From the Apennines, Italy
Authors: Lanari R. , Reitano R. , Faccenna C. , Agostinetti N. Piana , Ballato P.
Published: February 2023

The topography of orogenic belts responds to several contributions operating at short and long temporal and spatial (i.e., wavelengths) scales, from the surface to the deep mantle. Here, we aim to investigate the connection between morphometric characteristics, exhumation, and crustal deformation along and across the Italian Apennines, by comparing superficial with deeper data. Specifically, we present four sets of observations that are constructed by gathering previous data and adding new analyses and inferences, that include: (a) a new geomorphological set of analyses; (b) a database of available low temperature thermochronological cooling ages; (c) a reconstruction of drainage divide evolution in time and space based on the age of the youngest lacustrine deposits within each extensional basin; (d) Moho depth from receiver functions, gathering previous estimates and 13 new ones. From these sets of data, it emerges that across the main drainage divide of the Apennines, the morphological characteristics, the style of deformation and the spatial distribution of exhumation correlate with the geometries of the Moho and are associated with a strong asymmetry in the Northern‐Apennines and a clear symmetry in the Central‐Apennines. We interpret these results as evidence of a strong coupling between shallower and deeper geometries, that are most likely related to complex along‐strike variations in the Apennines geodynamic setting.
Effects of Large Macropores on Saline Water Evaporation From Marsh Soil
Authors: Xu Xinghua , Xin Pei , Zhou Tingzhang , Yu Xiayang
Published: February 2023

Macropores such as crab burrows are a common feature of salt marsh sediment and are recognized as an important factor influencing pore‐water flow in salt marshes. In this study, we examined the effect of macropores on saline water evaporation and pore‐water salinity based on laboratory experiments and numerical simulations. Soil columns with and without an artificial macropore were packed with clay‐loam and were set with different hydraulic heads fixed at the bottom. The results showed that increase in pore‐water salinity significantly reduced evaporation rates. The preferential flow induced by macropores recharged the soil surrounding macropores and maintained higher evaporation rates in comparison with homogeneous soil without macropores. As macropores induced lateral flow, the pore‐water salinity in shallow soil around the macropores was reduced but that in the area away from the macropores was increased. These impacts were more remarkable on the soil layers with higher hydraulic heads. A sensitivity analysis showed that with a higher initial pore‐water salinity, the macropore's impact on soil evaporation rates was more remarkable for both clay‐loam and silt‐loam. These results revealed the effect of macropores on soil evaporation processes and soil conditions, and also shed light on associated biogeochemical processes in salt marshes.
Boreal Trees May Grow Faster Due to Climate Change
Authors: Sidik Saima
Published: February 2023

Enhanced tree growth could significantly offset carbon emissions, but some researchers say it’s not enough to compete with forest disturbances.
Changes at glutamate tripartite synapses in the prefrontal cortex of a new animal model of resilience/vulnerability to acute stress
Authors: Bonifacino Tiziana , Mingardi Jessica , Facchinetti Roberta , Sala Nathalie , Frumento Giulia , Ndoj Elona , Valenza Marta , Paoli Caterina , Ieraci Alessandro , Torazza Carola , Balbi Matilde , Guerinoni Michele , Muhammad Nadeem , Russo Isabella , Milanese Marco , Scuderi Caterina , Barbon Alessandro , Steardo Luca , Bonanno Giambattista , Popoli Maurizio , Musazzi Laura
Published: February 2023

Stress represents a main risk factor for psychiatric disorders. Whereas it is known that even a single trauma may induce psychiatric disorders in humans, the mechanisms of vulnerability to acute stressors have been little investigated. In this study, we generated a new animal model of resilience/vulnerability to acute footshock (FS) stress in rats and analyzed early functional, molecular, and morphological determinants of stress vulnerability at tripartite glutamate synapses in the prefrontal cortex (PFC). We found that adult male rats subjected to FS can be deemed resilient (FS-R) or vulnerable (FS-V), based on their anhedonic phenotype 24 h after stress exposure, and that these two populations are phenotypically distinguishable up to two weeks afterwards. Basal presynaptic glutamate release was increased in the PFC of FS-V rats, while depolarization-evoked glutamate release and synapsin I phosphorylation at Ser9 were increased in both FS-R and FS-V. In FS-R and FS-V rats the synaptic expression of GluN2A and apical dendritic length of prelimbic PFC layers II–III pyramidal neurons were decreased, while BDNF expression was selectively reduced in FS-V. Depolarization-evoked (carrier-mediated) glutamate release from astroglia perisynaptic processes (gliosomes) was selectively increased in the PFC of FS-V rats, while GLT1 and xCt levels were higher and GS expression reduced in purified PFC gliosomes from FS-R. Overall, we show for the first time that the application of the sucrose intake test to rats exposed to acute FS led to the generation of a novel animal model of resilience/vulnerability to acute stress, which we used to identify early determinants of maladaptive response related to behavioral vulnerability to stress.
Evaluation of red-complex bacteria loads in complete denture patients: a pilot study
Authors: Veseli Enis , Staka Gloria , Tovani-Palone Marcos Roberto
Published: February 2023

Objective

This pilot study aimed to evaluate red-complex bacteria (RCB) loads in edentulous patients, before and after dentures’ insertion.

Materials and methods

Thirty patients were included in the study. Deoxyribonucleic acid (DNA) isolated from bacterial samples were obtained from the dorsum of the tongue before and 3 months after complete dentures (CDs) insertion in order to identify the presence of RCB (Tannerella forsythia, Porphyromonas gingivalis, and Treponema denticola) and quantify their loads, using real-time polymerase chain reaction (RT-PCR). Bacterial loads were represented as “Lg (genome equivalents/sample)” and the data classified according to the “ParodontoScreen” test.

Results

Significant changes in bacterial loads were observed before and 3 months after the CDs insertion for: P. gingivalis (0.40 ± 0.90 vs 1.29 ± 1.64, p = 0.0007), T. forsythia (0.36 ±0.94 vs 0.87 ± 1.45, p = 0.005), and T. denticola (0.11 ± 0.41 vs 0.33 ± 0.75, p = 0.03). Before the CDs insertion, all patients had a normal bacterial prevalence range (100%) for all analyzed bacteria. Three months after the insertion, 2 (6.7%) of them had a moderate bacterial prevalence range for P. gingivalis, while 28 (93.3%) had a normal bacterial prevalence range.

Conclusion

The use of CDs has a significant impact on increasing RCB loads in edentulous patients.
Delivery of microRNA-302a-3p by APTES modified hydroxyapatite nanoparticles to promote osteogenic differentiation in vitro
Authors: Limlawan Pirawish , Marger Laurine , Durual Stéphane , Vacharaksa Anjalee
Published: February 2023

Objective

To demonstrate the miRNA delivery by hydroxyapatite nanoparticles modified with APTES (HA-NPs-APTES) and promote osteogenic gene expression.

Materials and methods

Osteosarcoma cells (HOS, MG-63) and primary human mandibular osteoblasts (HmOBs) were co-cultured with HA-NPs-APTES conjugated with miRNA-302a-3p. Resazurin reduction assay was performed to evaluate HA-NPs-APTES biocompatibility. Intracellular uptake was demonstrated by confocal fluorescent and scanning electron microscopy. The miRNA-302a-3p and its mRNA targets expression levels including COUP-TFII and other osteogenic genes were assessed by qPCR on day1 or day5 post-delivery. Calcium deposition induced by the osteogenic gene upregulation was shown by alizarin red staining on day7 and 14 post-delivery.

Results

Proliferation of HOS cells treated with HA-NPs-APTES was similar to that of untreated cells. HA-NPs-APTES was visualized in cell cytoplasm within 24 hours. MiRNA-302a-3p level was upregulated in HOS, MG-63 and HmOBs as compared to untreated cells. As a result, COUP-TFII mRNA expression was reduced, followed by an increase of RUNX2 and other osteogenic genes mRNA expression. Calcium deposition induced by HA-NPs-APTES-miR-302a-3p in HmOBs was significantly higher than in untreated cells.

Conclusion

HA-NPs-APTES may support the delivery of miRNA-302a-3p into bone cells, as assessed by osteogenic gene expression and differentiation improvement once this combination is used on osteoblast cultures.
m5C-dependent cross-regulation between nuclear reader ALYREF and writer NSUN2 promotes urothelial bladder cancer malignancy through facilitating RABL6/TK1 mRNAs splicing and stabilization
Authors: Wang Ning , Chen Ri-xin , Deng Min-hua , Wei Wen-su , Zhou Zhao-hui , Ning Kang , Li Yong-hong , Li Xiang-dong , Ye Yun-lin , Wen Jun-hua , Dong Biao , Zhang Xue-pei , Liu Zhuo-wei , Zhou Fang-jian
Published: February 2023

The significance of 5-methylcytosine (m5C) methylation in human malignancies has become an increasing focus of investigation. Here, we show that m5C regulators including writers, readers and erasers, are predominantly upregulated in urothelial carcinoma of the bladder (UCB) derived from Sun Yat-sen University Cancer Center and The Cancer Genome Atlas cohort. In addition, NOP2/Sun RNA methyltransferase family member 2 (NSUN2) as a methyltransferase and Aly/REF export factor (ALYREF) as a nuclear m5C reader, are frequently coexpressed in UCB. By applying patient-derived organoids model and orthotopic xenograft mice model, we demonstrate that ALYREF enhances proliferation and invasion of UCB cells in an m5C-dependent manner. Integration of tanscriptome-wide RNA bisulphite sequencing (BisSeq), RNA-sequencing (RNA-seq) and RNA Immunoprecipitation (RIP)-seq analysis revealed that ALYREF specifically binds to hypermethylated m5C site in RAB, member RAS oncogene family like 6 (RABL6) and thymidine kinase 1 (TK1) mRNA via its K171 domain. ALYREF controls UCB malignancies through promoting hypermethylated RABL6 and TK1 mRNA for splicing and stabilization. Moreover, ALYREF recognizes hypermethylated m5C site of NSUN2, resulting in NSUN2 upregulation in UCB. Clinically, the patients with high coexpression of ALYREF/RABL6/TK1 axis had the poorest overall survival. Our study unveils an m5C dependent cross-regulation between nuclear reader ALYREF and m5C writer NSUN2 in activation of hypermethylated m5C oncogenic RNA through promoting splicing and maintaining stabilization, consequently leading to tumor progression, which provides profound insights into therapeutic strategy for UCB.
Reconstructing clonal tree for phylo-phenotypic characterization of cancer using single-cell transcriptomics
Authors: Jun Seong-Hwan , Toosi Hosein , Mold Jeff , Engblom Camilla , Chen Xinsong , O’Flanagan Ciara , Hagemann-Jensen Michael , Sandberg Rickard , Aparicio Samuel , Hartman Johan , Roth Andrew , Lagergren Jens
Published: February 2023

Functional characterization of the cancer clones can shed light on the evolutionary mechanisms driving cancer’s proliferation and relapse mechanisms. Single-cell RNA sequencing data provide grounds for understanding the functional state of cancer as a whole; however, much research remains to identify and reconstruct clonal relationships toward characterizing the changes in functions of individual clones. We present PhylEx that integrates bulk genomics data with co-occurrences of mutations from single-cell RNA sequencing data to reconstruct high-fidelity clonal trees. We evaluate PhylEx on synthetic and well-characterized high-grade serous ovarian cancer cell line datasets. PhylEx outperforms the state-of-the-art methods both when comparing capacity for clonal tree reconstruction and for identifying clones. We analyze high-grade serous ovarian cancer and breast cancer data to show that PhylEx exploits clonal expression profiles beyond what is possible with expression-based clustering methods and clear the way for accurate inference of clonal trees and robust phylo-phenotypic analysis of cancer.
Prolonged experimental CD4+ T-cell depletion does not cause disease progression in SIV-infected African green monkeys
Authors: Le Hingrat Quentin , Sette Paola , Xu Cuiling , Rahmberg Andrew R. , Tarnus Lilas , Annapureddy Haritha , Kleinman Adam , Brocca-Cofano Egidio , Sivanandham Ranjit , Sivanandham Sindhuja , He Tianyu , Capreri Daniel J. , Ma Dongzhu , Estes Jacob D. , Brenchley Jason M. , Apetrei Cristian , Pandrea Ivona
Published: February 2023

CD4+ T-cell depletion is a hallmark of HIV infection, leading to impairment of cellular immunity and opportunistic infections, but its contribution to SIV/HIV-associated gut dysfunction is unknown. Chronically SIV-infected African Green Monkeys (AGMs) partially recover mucosal CD4+ T-cells, maintain gut integrity and do not progress to AIDS. Here we assess the impact of prolonged, antibody-mediated CD4 + T-cell depletion on gut integrity and natural history of SIV infection in AGMs. All circulating CD4+ T-cells and >90% of mucosal CD4+ T-cells are depleted. Plasma viral loads and cell-associated viral RNA in tissues are lower in CD4+-cell-depleted animals. CD4+-cell-depleted AGMs maintain gut integrity, control immune activation and do not progress to AIDS. We thus conclude that CD4+ T-cell depletion is not a determinant of SIV-related gut dysfunction, when gastrointestinal tract epithelial damage and inflammation are absent, suggesting that disease progression and resistance to AIDS are independent of CD4+ T-cell restoration in SIVagm-infected AGMs.
Cross-stress gene expression atlas of Marchantia polymorpha reveals the hierarchy and regulatory principles of abiotic stress responses
Authors: Tan Qiao Wen , Lim Peng Ken , Chen Zhong , Pasha Asher , Provart Nicholas , Arend Marius , Nikoloski Zoran , Mutwil Marek
Published: February 2023

Abiotic stresses negatively impact ecosystems and the yield of crops, and climate change will increase their frequency and intensity. Despite progress in understanding how plants respond to individual stresses, our knowledge of plant acclimatization to combined stresses typically occurring in nature is still lacking. Here, we used a plant with minimal regulatory network redundancy,Marchantia polymorpha, to study how seven abiotic stresses, alone and in 19 pairwise combinations, affect the phenotype, gene expression, and activity of cellular pathways. While the transcriptomic responses show a conserved differential gene expression betweenArabidopsisandMarchantia, we also observe a strong functional and transcriptional divergence between the two species. The reconstructed high-confidence gene regulatory network demonstrates that the response to specific stresses dominates those of others by relying on a large ensemble of transcription factors. We also show that a regression model could accurately predict the gene expression under combined stresses, indicating thatMarchantiaperforms arithmetic multiplication to respond to multiple stresses. Lastly, two online resources (https://conekt.plant.toolsandhttp://bar.utoronto.ca/efp_marchantia/cgi-bin/efpWeb.cgi) are provided to facilitate the study of gene expression inMarchantiaexposed to abiotic stresses.
The ϕPA3 phage nucleus is enclosed by a self-assembling 2D crystalline lattice
Authors: Nieweglowska Eliza S. , Brilot Axel F. , Méndez-Moran Melissa , Kokontis Claire , Baek Minkyung , Li Junrui , Cheng Yifan , Baker David , Bondy-Denomy Joseph , Agard David A.
Published: February 2023

To protect themselves from host attack, numerous jumbo bacteriophages establish a phage nucleus—a micron-scale, proteinaceous structure encompassing the replicating phage DNA. Bacteriophage and host proteins associated with replication and transcription are concentrated inside the phage nucleus while other phage and host proteins are excluded, including CRISPR-Cas and restriction endonuclease host defense systems. Here, we show that nucleus fragments isolated from ϕPA3 infected Pseudomonas aeruginosa form a 2-dimensional lattice, having p2 or p4 symmetry. We further demonstrate that recombinantly purified primary Phage Nuclear Enclosure (PhuN) protein spontaneously assembles into similar 2D sheets with p2 and p4 symmetry. We resolve the dominant p2 symmetric state to 3.9 Å by cryo-EM. Our structure reveals a two-domain core, organized into quasi-symmetric tetramers. Flexible loops and termini mediate adaptable inter-tetramer contacts that drive subunit assembly into a lattice and enable the adoption of different symmetric states. While the interfaces between subunits are mostly well packed, two are open, forming channels that likely have functional implications for the transport of proteins, mRNA, and small molecules.
Associations of timing of physical activity with all-cause and cause-specific mortality in a prospective cohort study
Authors: Feng Hongliang , Yang Lulu , Liang Yannis Yan , Ai Sizhi , Liu Yaping , Liu Yue , Jin Xinyi , Lei Binbin , Wang Jing , Zheng Nana , Chen Xinru , Chan Joey W. Y. , Sum Raymond Kim Wai , Chan Ngan Yin , Tan Xiao , Benedict Christian , Wing Yun Kwok , Zhang Jihui
Published: February 2023

There is a growing interest in the role of timing of daily behaviors in improving health. However, little is known about the optimal timing of physical activity to maximize health benefits. We perform a cohort study of 92,139 UK Biobank participants with valid accelerometer data and all-cause and cause-specific mortality outcomes, comprising over 7 years of median follow-up (638,825 person-years). Moderate-to-vigorous intensity physical activity (MVPA) at any time of day is associated with lower risks for all-cause, cardiovascular disease, and cancer mortality. In addition, compared with morning group (>50% of daily MVPA during 05:00-11:00), midday-afternoon (11:00-17:00) and mixed MVPA timing groups, but not evening group (17:00-24:00), have lower risks of all-cause and cardiovascular disease mortality. These protective associations are more pronounced among the elderly, males, less physically active participants, or those with preexisting cardiovascular diseases. Here, we show that MVPA timing may have the potential to improve public health.
Autophagy inhibition prevents lymphatic malformation progression to lymphangiosarcoma by decreasing osteopontin and Stat3 signaling
Authors: Yang Fuchun , Kalantari Shiva , Ruan Banzhan , Sun Shaogang , Bian Zhaoqun , Guan Jun-Lin
Published: February 2023

Lymphatic malformation (LM) is a vascular anomaly originating from lymphatic endothelial cells (ECs). While it mostly remains a benign disease, a fraction of LM patients progresses to malignant lymphangiosarcoma (LAS). However, very little is known about underlying mechanisms regulating LM malignant transformation to LAS. Here, we investigate the role of autophagy in LAS development by generating EC-specific conditional knockout of an essential autophagy gene Rb1cc1/FIP200 in Tsc1iΔEC mouse model for human LAS. We find that Fip200 deletion blocked LM progression to LAS without affecting LM development. We further show that inhibiting autophagy by genetical ablation of FIP200, Atg5 or Atg7, significantly inhibited LAS tumor cell proliferation in vitro and tumorigenicity in vivo. Transcriptional profiling of autophagy-deficient tumor cells and additional mechanistic analysis determine that autophagy plays a role in regulating Osteopontin expression and its down-stream Jak/Stat3 signaling in tumor cell proliferation and tumorigenicity. Lastly, we show that specifically disrupting FIP200 canonical autophagy function by knocking-in FIP200−4A mutant allele in Tsc1iΔEC mice blocked LM progression to LAS. These results demonstrate a role for autophagy in LAS development, suggesting new strategies for preventing and treating LAS.
The Toxoplasma micropore mediates endocytosis for selective nutrient salvage from host cell compartments
Authors: Wan Wenyan , Dong Hui , Lai De-Hua , Yang Jiong , He Kai , Tang Xiaoyan , Liu Qun , Hide Geoff , Zhu Xing-Quan , Sibley L. David , Lun Zhao-Rong , Long Shaojun
Published: February 2023

Apicomplexan parasite growth and replication relies on nutrient acquisition from host cells, in which intracellular multiplication occurs, yet the mechanisms that underlie the nutrient salvage remain elusive. Numerous ultrastructural studies have documented a plasma membrane invagination with a dense neck, termed the micropore, on the surface of intracellular parasites. However, the function of this structure remains unknown. Here we validate the micropore as an essential organelle for endocytosis of nutrients from the host cell cytosol and Golgi in the model apicomplexan Toxoplasma gondii. Detailed analyses demonstrated that Kelch13 is localized at the dense neck of the organelle and functions as a protein hub at the micropore for endocytic uptake. Intriguingly, maximal activity of the micropore requires the ceramide de novo synthesis pathway in the parasite. Thus, this study provides insights into the machinery underlying acquisition of host cell-derived nutrients by apicomplexan parasites that are otherwise sequestered from host cell compartments.
Structural remodelling of the carbon–phosphorus lyase machinery by a dual ABC ATPase
Authors: Amstrup Søren K. , Ong Sui Ching , Sofos Nicholas , Karlsen Jesper L. , Skjerning Ragnhild B. , Boesen Thomas , Enghild Jan J. , Hove-Jensen Bjarne , Brodersen Ditlev E.
Published: February 2023

In Escherichia coli, the 14-cistron phn operon encoding carbon-phosphorus lyase allows for utilisation of phosphorus from a wide range of stable phosphonate compounds containing a C-P bond. As part of a complex, multi-step pathway, the PhnJ subunit was shown to cleave the C-P bond via a radical mechanism, however, the details of the reaction could not immediately be reconciled with the crystal structure of a 220 kDa PhnGHIJ C-P lyase core complex, leaving a significant gap in our understanding of phosphonate breakdown in bacteria. Here, we show using single-particle cryogenic electron microscopy that PhnJ mediates binding of a double dimer of the ATP-binding cassette proteins, PhnK and PhnL, to the core complex. ATP hydrolysis induces drastic structural remodelling leading to opening of the core complex and reconfiguration of a metal-binding and putative active site located at the interface between the PhnI and PhnJ subunits.
GSDME-mediated pyroptosis promotes the progression and associated inflammation of atherosclerosis
Authors: Wei Yuanyuan , Lan Beidi , Zheng Tao , Yang Lin , Zhang Xiaoxia , Cheng Lele , Tuerhongjiang Gulinigaer , Yuan Zuyi , Wu Yue
Published: February 2023

Pyroptosis, a type of Gasdermin-mediated cell death, contributes to an exacerbation of inflammation. To test the hypothesis that GSDME-mediated pyroptosis aggravates the progression of atherosclerosis, we generate ApoE and GSDME dual deficiency mice. As compared with the control mice, GSDME−/−/ApoE−/− mice show a reduction of atherosclerotic lesion area and inflammatory response when induced with a high-fat diet. Human atherosclerosis single-cell transcriptome analysis demonstrates that GSDME is mainly expressed in macrophages. In vitro, oxidized low-density lipoprotein (ox-LDL) induces GSDME expression and pyroptosis in macrophages. Mechanistically, ablation of GSDME in macrophages represses ox-LDL-induced inflammation and macrophage pyroptosis. Moreover, the signal transducer and activator of transcription 3 (STAT3) directly correlates with and positively regulates GSDME expression. This study explores the transcriptional mechanisms of GSDME during atherosclerosis development and indicates that GSDME-mediated pyroptosis in the progression of atherosclerosis could be a potential therapeutic approach for atherosclerosis.
Intelligent metasurface system for automatic tracking of moving targets and wireless communications based on computer vision
Authors: Li Weihan , Ma Qian , Liu Che , Zhang Yunfeng , Wu Xianning , Wang Jiawei , Gao Shizhao , Qiu Tianshuo , Liu Tonghao , Xiao Qiang , Wei Jiaxuan , Gu Ting Ting , Zhou Zhize , Li Fashuai , Cheng Qiang , Li Lianlin , Tang Wenxuan , Cui Tie Jun
Published: February 2023

The fifth-generation (5G) wireless communication has an urgent need for target tracking. Digital programmable metasurface (DPM) may offer an intelligent and efficient solution owing to its powerful and flexible controls of electromagnetic waves and advantages of lower cost, less complexity and smaller size than the traditional antenna array. Here, we report an intelligent metasurface system to perform target tracking and wireless communications, in which computer vision integrated with a convolutional neural network (CNN) is used to automatically detect the locations of moving targets, and the dual-polarized DPM integrated with a pre-trained artificial neural network (ANN) serves to realize the smart beam tracking and wireless communications. Three groups of experiments are conducted for demonstrating the intelligent system: detection and identification of moving targets, detection of radio-frequency signals, and real-time wireless communications. The proposed method sets the stage for an integrated implementation of target identification, radio environment tracking, and wireless communications. This strategy opens up an avenue for intelligent wireless networks and self-adaptive systems.
Chromium-catalyzed stereodivergent E- and Z-selective alkyne hydrogenation controlled by cyclic (alkyl)(amino)carbene ligands
Authors: Ling Liang , Hu Chenyang , Long Linhong , Zhang Xue , Zhao Lixing , Liu Liu Leo , Chen Hui , Luo Meiming , Zeng Xiaoming
Published: February 2023

The hydrogenation of alkynes allows the synthesis of olefins, which are important feedstock for the materials, pharmaceutical, and petrochemical industry. Thus, methods that enable this transformation via low-cost metal catalysis are desirable. However, achieving stereochemical control in this reaction is a long-standing challenge. Here, we report on the chromium-catalyzedE- andZ-selective olefin synthesis via hydrogenation of alkynes, controlled by two carbene ligands. A cyclic (alkyl)(amino)carbene ligand that contains a phosphino anchor enables the hydrogenation of alkynes in atrans-addition manner, selectively formingE-olefins. With an imino anchor-incorporated carbene ligand, the stereoselectivity can be switched, giving mainlyZ-isomers. This ligand-enabled geometrical stereoinversion strategy by one metal catalysis overrides common methods in control of theE- andZ-selectivity with two different metal catalysis, allowing for highly efficient and on-demand access to bothE- andZ-olefins in a stereo-complementary fashion. Mechanistic studies indicate that the different steric effect between these two carbene ligands may mainly dominate the selective formingE- orZ-olefins in control of the stereochemistry.
Topical phage therapy in a mouse model of Cutibacterium acnes-induced acne-like lesions
Authors: Rimon Amit , Rakov Chani , Lerer Vanda , Sheffer-Levi Sivan , Oren Sivan Alkalay , Shlomov Tehila , Shasha Lihi , Lubin Ruth , Zubeidat Khaled , Jaber Nora , Mujahed Musa , Wilensky Asaf , Coppenhagen-Glazer Shunit , Molho-Pessach Vered , Hazan Ronen
Published: February 2023

Acne vulgaris is a common neutrophil-driven inflammatory skin disorder in which Cutibacterium acnes (C. acnes) is known to play a key role. For decades, antibiotics have been widely employed to treat acne vulgaris, inevitably resulting in increased bacterial antibiotic resistance. Phage therapy is a promising strategy to combat the growing challenge of antibiotic-resistant bacteria, utilizing viruses that specifically lyse bacteria. Herein, we explore the feasibility of phage therapy against C. acnes. Eight novel phages, isolated in our laboratory, and commonly used antibiotics eradicate 100% of clinically isolated C. acnes strains. Topical phage therapy in a C. acnes-induced acne-like lesions mouse model affords significantly superior clinical and histological scores. Moreover, the decrease in inflammatory response was reflected by the reduced expression of chemokine CXCL2, neutrophil infiltration, and other inflammatory cytokines when compared with the infected-untreated group. Overall, these findings indicate the potential of phage therapy for acne vulgaris as an additional tool to conventional antibiotics.
Compilation and scaling strategies for a silicon quantum processor with sparse two-dimensional connectivity
Authors: Crawford O. , Cruise J. R. , Mertig N. , Gonzalez-Zalba M. F.
Published: February 2023

Inspired by the challenge of scaling-up existing silicon quantum hardware, we propose a 2d spin-qubit architecture with low compilation overhead. The architecture is based on silicon nanowire split-gate transistors which form 1d chains of spin-qubits and allow the execution of two-qubit operations among neighbors. We introduce a silicon junction which can couple four nanowires into 2d arrangements via spin shuttling andSwapoperations. We then propose a modular sparse 2d spin-qubit architecture with unit cells of diagonally-oriented squares with nanowires along the edges and junctions on the corners. Targeting noisy intermediate-scale quantum (NISQ) demonstrators, we show that the proposed architecture allows for compilation strategies which outperform methods for 1d chains, and exhibits favorable scaling properties which enable trading-off compilation overhead and colocation of control electronics within each square by adjusting the nanowire length. An appealing feature of the proposed architecture is its manufacturability using complementary-metal-oxide-semiconductor (CMOS) fabrication processes.
Deterministic improvements of quantum measurements with grouping of compatible operators, non-local transformations, and covariance estimates
Authors: Yen Tzu-Ching , Ganeshram Aadithya , Izmaylov Artur F.
Published: February 2023

Obtaining the expectation value of an observable on a quantum computer is a crucial step in the variational quantum algorithms. For complicated observables such as molecular electronic Hamiltonians, one of the strategies is to present the observable as a linear combination of measurable fragments. The main problem of this approach is a large number of measurements required for accurate estimation of the observable’s expectation value. We consider three previously studied directions that minimize the number of measurements: (1) grouping commuting operators using the greedy approach, (2) involving non-local unitary transformations for measuring, and (3) taking advantage of compatibility of some Pauli products with several measurable groups. The last direction gives rise to a general framework that not only provides improvements over previous methods but also connects measurement grouping approaches with recent advances in techniques of shadow tomography. Following this direction, we develop two measurement schemes that achieve a severalfold reduction in the number of measurements for a set of model molecules compared to previous state-of-the-art methods.