bluuebunny/crossref_metadata_2025 huggingface dataset:
Response surface optimization of a cardioprotective compound through pharmacosomal drug delivery system: in vivo bioavailability and cardioprotective activity potential
Authors: Dawoud Marwa H. S. , Zaafan Mai A. , Saleh Sarah S. , Mannaa Islam M. , Sweed Nabila M.
Published: April 2023

Vanillic acid (VA) is a phenolic compound with potential antioxidant activity, which improves ischemia-induced myocardial degeneration, by reducing oxidative stress; however, it suffers poor bioavailability owing to its poor solubility. VA-loaded pharmacosomes were optimized using a central composite design, where the effect of phosphatidylcholine:VA molar ratio and the precursor concentration were studied. An optimized formulation (O1) was prepared and tested for the release rate of VA, in vivo bioavailability, and cardioprotective potential on myocardial infarction-induced rats. The optimized formulation showed a particle size of 229.7 nm, polydispersity index of 0.29, and zeta potential of − 30 mV. O1 showed a sustained drug release for 48 h. The HPLC–UV method was developed for the determination of VA in plasma samples using protein precipitation. The optimized formulation showed a great improvement in the bioavailability as compared to VA. The residence time of the optimized formula was 3 times longer than VA. The optimized formulation showed a more potent cardioprotective effect as compared to VA, via inhibition of the MAPK pathway with subsequent inhibition of PI3k/NF-κB signaling, in addition to its antioxidant effect. The optimized formulation showed normalization of many oxidative stress and inflammatory biomarkers. Thus, a VA-loaded pharmacosome formulation with promising bioavailability and cardioprotective activity potential was prepared.

Graphical Abstract
Real logarithms of semi-simple matrices
Authors: Pertici Donato
Published: April 2023

We study the differential and topological structures of the set of real logarithms of any semi-simple non-singular matrix and of the set of real skew-symmetric logarithms of any special orthogonal matrix.
Numerical studies to detect chaotic motion in the full planar averaged three-body problem
Authors: Di Ruzza Sara
Published: April 2023

In this paper, the author deals with a well-known problem of Celestial Mechanics, namely the three-body problem. A numerical analysis has been done in order to prove existence of chaotic motions of the full-averaged problem in particular configurations. Full because all the three bodies have non-negligible masses and averaged because the Hamiltonian describing the system has been averaged with respect to a fast angle. A reduction of degrees of freedom and of the phase-space is performed in order to apply the notion of covering relations and symbolic dynamics.
The Impact of Youth Digital Citizenship Education: Insights from a Cluster Randomized Controlled Trial Outcome Evaluation of the Be Internet Awesome (BIA) Curriculum
Authors: Jones Lisa M. , Mitchell Kimberly J. , Beseler Cheryl L.
Published: April 2023

School psychologists and other school professionals are increasingly turning to digital citizenship programs to improve children’s online safety. However, to date, there has been no rigorous outcome evaluation of these programs. The current study used a cluster randomized control trial methodology (CRCT) to evaluate the impact of the Be Internet Awesome digital citizenship program on knowledge, attitudinal, and behavioral outcomes for 1072 4th–6th graders at 14 participating schools (7 treatment and 7 control schools). Multilevel logistic, multinomial, and Gaussian models were used to test outcomes. The study found support for program impact on children’s knowledge of new online safety concepts and self-efficacy for handling online problems relative to students in control conditions. However, no program impact was found for other outcomes including online privacy or civility, cyberbullying, and talking with parents about online problems. Findings highlight the need for clarity on digital citizenship program goals, innovative approaches, and increased evaluation research.
Probabilistic prediction with locally weighted jackknife predictive system
Authors: Wang Di , Wang Ping , Wang Pingping , Wang Cong , He Zhen , Zhang Wei
Published: April 2023

Probabilistic predictions for regression problems are more popular than point predictions and interval predictions, since they contain more information for test labels. Conformal predictive system is a recently proposed non-parametric method to do reliable probabilistic predictions, which is computationally inefficient due to its learning process. To build faster conformal predictive system and make full use of training data, this paper proposes the predictive system based on locally weighted jackknife prediction approach. The theoretical property of our proposed method is proved with some regularity assumptions in the asymptotic setting, which extends our earlier theoretical researches from interval predictions to probabilistic predictions. In the experimental section, our method is implemented based on our theoretical analysis and its comparison with other predictive systems is conducted using 20 public data sets. The continuous ranked probability scores of the predictive distributions and the performance of the derived prediction intervals are compared. The better performance of our proposed method is confirmed with Wilcoxon tests. The experimental results demonstrate that the predictive system we proposed is not only empirically valid, but also provides more information than the other comparison predictive systems.
Transverse Dynamics of Two-Dimensional Traveling Periodic Gravity–Capillary Water Waves
Authors: Haragus Mariana , Truong Tien , Wahlén Erik
Published: April 2023

We study the transverse dynamics of two-dimensional traveling periodic waves for the gravity–capillary water-wave problem. The governing equations are the Euler equations for the irrotational flow of an inviscid fluid layer with free surface under the forces of gravity and surface tension. We focus on two open sets of dimensionless parameters $$(\alpha ,\beta )$$

(
α
,
β
)

, where $$\alpha $$
α
and $$\beta $$
β
are the inverse square of the Froude number and the Weber number, respectively. For each arbitrary but fixed pair $$(\alpha ,\beta )$$

(
α
,
β
)

in one of these sets, two-dimensional traveling periodic waves bifurcate from the trivial constant flow. In one open set we find a one-parameter family of periodic waves, whereas in the other open set we find two geometrically distinct one-parameter families of periodic waves. Starting from a transverse spatial dynamics formulation of the governing equations, we investigate the transverse linear instability of these periodic waves and the induced dimension-breaking bifurcation. The two results share a common analysis of the purely imaginary spectrum of the linearization at a periodic wave. We apply a simple general criterion for the transverse linear instability problem and a Lyapunov center theorem for the dimension-breaking bifurcation. For parameters $$(\alpha ,\beta )$$

(
α
,
β
)

in the open set where there is only one family of periodic waves, we prove that these waves are linearly transversely unstable. For the other open set, we show that the waves with larger wavenumber are transversely linearly unstable. We also identify an open subset of parameters for which both families of periodic waves are transversely linearly unstable. For each of these transversely linearly unstable periodic waves, a dimension-breaking bifurcation occurs in which three-dimensional doubly periodic waves bifurcate from the two-dimensional periodic wave.
Evaluating the influence of wrapping turns for a new packaging method called sustainable specific suspension (3S) packaging
Authors: Nica Ward , Verschueren Gilles , Roman Jannes , Slaets Peter , Juwet Marc
Published: April 2023

3S packaging, which stands for sustainable specific suspension packaging, wraps a product on a piece of cardboard using stretch wrap film. This cardboard is then folded and slipped into a box. The product is protected on all six sides by air if impact forces occur. This research focuses on the number of wraps needed to keep the peak acceleration lower than the maximum acceleration that can be tolerated by the product. A new test method is presented, based on existing drop test methods. It is shown that the protection in one specific shock direction (perpendicular to the tray length) is much more affected by the number of wraps than the other, lengthwise, direction. This allows for a focus on that direction when optimizing the number of wraps. The variation in the measured acceleration peaks and the sudden change in acceleration indicate that the package has reached the protection limits and contact is made between the object and the enveloping cardboard box. Combined with the required degree of protection, one can evaluate whether the object is sufficiently protected.
Building a community-scale plastic recycling station to make flower pots from bottle caps
Authors: Chaari Mohamed Zied , Abdelfatah Mohamed , Al-Sulaiti Salman , Daroge Fawwad , Al-Rahimi Rashid , Pereira Gilroy
Published: April 2023

Plastic waste is increasing worldwide, contributing significantly to pollution and global warming. Our department uses at least 50 plastic water bottles daily; these bottles can be reused to manufacture other products. Recycling plastic waste produces various products, including garden sets for kids, bricks, roof tiles, key holders, and flowerpots. Through this project, we contribute to the fight against pollution caused by plastic waste by developing an easy-to-use plastic processing system. We create these valuable products using plastic collected from landfills. We present an open-source system that can be easily built by a technical team to create an ecosystem. We use the project as a mobile educational model to demonstrate the recycling mechanism and to foster a community recycling culture. The following procedures are included in this study. High-density polyethylene bottle caps are washed and dried before shredding in a shredder to produce flakes. Plastic flakes are fed into an extruder, which heats and transforms them into a homogeneous mass. This molten plastic is molded into the shape of a flowerpot using a die. Pots are great products to obtain from discarded plastic caps due to their strength. Following the fabrication of the entire system, numerous tests are performed to improve the design and obtain the desired specifications, resulting in appealing end products. In our facilities, flowerpots are made from consumer bottle caps and used to grow aloe.
Saying What the Law Is
Authors: Bernstein Anya
Published: April 2023

Exploring what it means to take formal law as an ethnographic object—a social phenomenon that both reflects and affects the society that produced it—this article analyzes the legal doctrine governing the judicial review of agency action. This doctrine is split into two streams: one evaluates agency interpretations of law, the other, agency policy decisions. In choosing to use one or the other, courts thus implicitly categorize the agency action under review as either interpretation or implementation. As interviews with agency administrators underline, however, these categories do not map onto the structure of agency action. Neither do they reflect the qualities of legal language. Rather than reacting to the inherent realities of their object, these doctrines instantiate a language ideology that pits the saying of law against the doing of it. After a brief introduction to language ideologies, I show some linguistic and legal realities that this particular one erases, and trace its recursive ramification in other areas of legal thought. Obscuring the speech-act nature of law, the saying-versus-doing language ideology helps commentators paint a picture of ideal judges as neutral, passive interpreters who merely report on the inherent meaning of law, as opposed to less ideal others who implement policies that change it. I also consider what a new language ideology—one that recognizes that the meaning of legal language emerges in part through its effects in the world—might do.
Depiction as possible phase in the dynamics of sociomorphing
Authors: Seibt Johanna
Published: April 2023

The depiction model presents a major advance in our theoretical conceptualization of how humans experience and understand social robots. But the scope of the model is, I suggest, more limited: It pertains to one possible phase in a more comprehensive cognitive-practical dynamics of sense-making (“sociomorphing”) as conceptualized in the OASIS framework. According to the OASIS framework, some basic social actions can be realized by robots, while others may be depicted in the way described by the model.
When Pinocchio becomes a real boy: Capability and felicity in AI and interactive depictions
Authors: Carroll John M.
Published: April 2023

Clark and Fischer analyze social robots as interactive depictions, presenting characters that people can interact with in social settings. Unlike other types of depictions, the props for social robot depictions depend on emerging interactive technologies. This raises questions about how such depictions depict: They conflate character and prop in ways that delight, confuse, mistreat, and may become ordinary human–technology interactions.
Meta-cognition about social robots could be difficult, making self-reports about some cognitive processes less useful
Authors: Rueben Matthew
Published: April 2023

There are reasons to suspect that meta-cognition about construing social robots as depictions would be more difficult – or absent – than Clark and Fischer discuss. Self-reports about the cognitive processes involved might therefore tend to be incomplete or inaccurate, limiting their usefulness as measures.
Social robots and the intentional stance
Authors: Veit Walter , Browning Heather
Published: April 2023

Why is it that people simultaneously treat social robots as mere designed artefacts, yet show willingness to interact with them as if they were real agents? Here, we argue that Dennett's distinction between the intentional stance and the design stance can help us to resolve this puzzle, allowing us to further our understanding of social robots as interactive depictions.
On the potentials of interaction breakdowns for HRI
Authors: Wrede Britta , Vollmer Anna-Lisa , Krach Sören
Published: April 2023

How do we switch between “playing along” and treating robots as technical agents? We propose interaction breakdowns to help solve this “social artifact puzzle”: Breaks cause changes from fluid interaction to explicit reasoning and interaction with the raw artifact. These changes are closely linked to understanding the technical architecture and could be used to design better human–robot interaction (HRI).
Fictional emotions and emotional reactions to social robots as depictions of social agents
Authors: Blatter Jonas , Weber-Guskar Eva
Published: April 2023

Following the depiction theory by Clark and Fischer we would expect people interacting with robots to experience fictional emotions akin to those toward films or novels. However, some people's emotional reactions toward robots display the motivational force typical to non-fictional emotions. We discuss this incongruity and offer two suggestions on how to explain it while maintaining the depiction theory.
High‐Tide Flooding Along the China Coastline: Past and Future
Authors: Li S. , Wahl T. , Fang J. , Liu L. , Jiang T.
Published: April 2023

Coastal flooding has become a major issue for low‐lying coastal cities in China, and a lot of research has focused on assessing flood risk from storms and associated extreme sea levels. High‐tide flooding (HTF), however, which leads to minor inundation and occurs more frequently as sea level continues to rise has not been assessed comprehensively. Here, we analyze HTF along the China coastline using tide gauge records. We show that the frequency of HTF has increased (Xiamen doubled HTF frequency every 11.5–37.4 years, with the median being 17.5 years). As a result, the cumulative loss ratios of HTF are higher than those of major (or extreme) flooding events in several locations. To gain insights into the processes driving HTF changes, we decompose still water levels that occurred during HTF into five components, including non‐linear trend, interannual to decadal mean sea level (MSL) variability, seasonal MSL cycle, tidal anomaly, and nontidal residuals. It is evident that due to sea‐level rise (SLR) fewer components need to combine to raise the water levels above HTF thresholds. We show that the South China Sea coast already experiences HTF purely driven by high spring tides, and will also see the fastest future increase in the number of tide‐only HTF events. In general, China will experience more HTF days under all warming scenarios as SLRs. This long‐term trend will be modulated by the nodal cycle of ocean tides leading to more rapid increases in HTF in the 2030s and 2050s.
Diverse Response of Western North Pacific Anticyclone to Fast‐Decay El Niño During Decaying Summer
Authors: Jiang Leishan , Chen Han‐Ching , Li Tim , Chen Lin
Published: April 2023

Previous studies suggested that fast‐decay El Niño events are more favorable in generating the western North Pacific anticyclone (WNPAC) in the decaying summer. However, we found that this is not the case for all fast‐decay El Niño events. By comparing two groups of fast‐decay El Niño events with significant and insignificant WNPAC in the following summer, we found that the westward extension of the equatorial Pacific cold sea surface temperature anomalies (SSTA) and the subtropical central‐north Pacific cold SSTA play important roles in the generation and intensification of the WNPAC during decaying summer. Further analyses indicated that the internal atmospheric mode—North Pacific Oscillation during boreal spring can affect the formation of the cold SSTA over the subtropical central‐north Pacific and the westward extension of the equatorial Pacific cold SSTA during summer. Additional effects of tropical Indian and Atlantic forcing on the maintenance of the WNPAC are also shown.
The Rate of Canopy Development Modulates the Link Between the Timing of Spring Leaf Emergence and Summer Moisture
Authors: Denham Sander O. , Barnes Mallory L. , Chang Qing , Korolev Mitchell , Wood Jeffery D. , Oishi A. Christopher , Shay Kathryn O. , Stoy Paul C. , Chen Jiquan , Novick Kimberly A.
Published: April 2023

Shifts in phenological timing have important implications for ecosystem processes, with spring leaf emergence as a dominant control of carbon, water, and energy cycling. Phenological events are predominantly determined by weather and climate, therefore dynamic in time and sensitive to climate feedbacks. Improving our understanding of how ecosystems respond to changes in phenological timing will enhance our ability to assess summer soil water availability, since the timing of spring leaf emergence may lead to soil moisture deficits later in the growing season. We leveraged data from five AmeriFlux towers in central and eastern United States to investigate the extent spring leaf emergence (i.e., start of spring, SoS) influences rates at which forest canopies develop and how this impacts summer soil moisture (θJJA) variability. Our results indicate that ecosystem processes, specifically gross primary production (GPP) and evapotranspiration (ET), exhibit compensatory responses to varying leaf emergence; with delayed spring‐onset, the canopy developed more quickly, resulting in rapid GPP and ET increases, consistent across sites. Nonetheless, early SoS is a relatively good indicator for potential summer soil water deficits, particularly when it occurs together with meteorological conditions (i.e., lower‐than‐average precipitation, hot summer temperatures) that contribute to soil water deficits. When these meteorological conditions coincide with early SoS, θJJA deficits are exacerbated. To the extent that these extreme conditions occur more frequently under future climate scenarios, the dynamics of spring phenology and hydroclimate may play an increasingly important role in portending the likelihood of summer water deficits, which are projected to become more severe.
Thermo‐Kinematic Evolution of the Eastern European Alps Along the TRANSALP Transect
Authors: Eizenhöfer Paul R. , Glotzbach Christoph , Kley Jonas , Ehlers Todd A.
Published: April 2023

The eastern European Alps are shaped by the indentation of Adria into Europe. Recent tomography, depicting detached slab fragments, has been interpreted as evidence of continuous southward subduction of European lithosphere, contrary to an often‐invoked subduction polarity reversal. Orogen‐scale exhumation, driven by rock displacement along active faults, may reflect subduction polarity within the framework of doubly‐vergent Coulomb wedge theory, provided the absence of rheological contrasts across the colliding plates. Low‐temperature thermochronology can evaluate crustal cooling in response to changes in tectonic and erosional boundary conditions. This study investigates the consistency of observed crustal re‐organization, exhumation, and mantle processes in the Eastern Alps. Thermo‐kinematic forward models driven by reconstructions of crustal shortening along the TRANSALP geophysical transect were subjected to variations in shortening rates, thermophysical parameters, and topographic evolution, supplemented by new fission‐track data. The thermo‐kinematic models reproduce: (a) the orogen‐scale structural geometry, (b) the distribution of thermochronometer ages, (c) observed time‐temperature paths, and (f) the present‐day surface heat flux. Results suggest that exhumation is driven by rock displacement along active faults without the need to involve mantle‐driven buoyancy forces. Taken together, the results identify two possible scenarios: if the Tauern Ramp is a retro‐thrust and the southward shift of deformation in the Southern Alps is a response to new Coulomb‐wedge conditions, then our results support a Mid‐Miocene reversal of the subduction polarity. Alternatively, crustal deformation does not reflect mantle processes entailing a high degree of inter‐plate decoupling.
3D-printing-assisted flexible pressure sensor with a concentric circle pattern and high sensitivity for health monitoring
Authors: Lee Jihun , So Hongyun
Published: April 2023

In this study, a flexible pressure sensor is fabricated using polydimethylsiloxane (PDMS) with a concentric circle pattern (CCP) obtained through a fused deposition modeling (FDM)-type three-dimensional (3D) printer and poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) as the active layer. Through layer-by-layer additive manufacturing, the CCP surface is generated from a thin cone model with a rough surface by the FDM-type 3D printer. A novel compression method is employed to convert the cone shape into a planar microstructure above the glass transition temperature of a polylactic acid (PLA) filament. To endow the CCP surface with conductivity, PDMS is used to replicate the compressed PLA, and PEDOT:PSS is coated by drop-casting. The size of the CCP is controlled by changing the printing layer height (PLH), which is one of the 3D printing parameters. The sensitivity increases as the PLH increases, and the pressure sensor with a 0.16 mm PLH exhibits outstanding sensitivity (160 kPa−1), corresponding to a linear pressure range of 0–0.577 kPa with a good linearity of R2 = 0.978, compared to other PLHs. This pressure sensor exhibits stable and repeatable operation under various pressures and durability under 6.56 kPa for 4000 cycles. Finally, monitoring of various health signals such as those for the wrist pulse, swallowing, and pronunciation of words is demonstrated as an application. These results support the simple fabrication of a highly sensitive, flexible pressure sensor for human health monitoring.
The preterm gut microbiota and administration routes of different probiotics: a randomized controlled trial
Authors: Rahkola Ella-Noora , Rautava Samuli , Hiltunen Henni , Ross Chandler , Lahti Leo , Isolauri Erika
Published: April 2023

Background

Preterm children with their aberrant gut microbiota and susceptibility to infections and inflammation constitute a considerable target group for probiotic therapy to generate the age-appropriate healthy microbiota.

Methods

68 preterm neonates were randomized into five intervention groups: Beginning from the median age of 3 days, 13 children received Lactobacillus rhamnosus GG (LGG) directly orally, and 17 via the lactating mother. 14 children received LGG with Bifidobacterium lactis Bb-12 (Bb12) orally, and 10 via the lactating mother. 14 children received placebo. The children’s faecal microbiota was assessed at the age of 7 days by 16S rRNA gene sequencing.

Results

The gut microbiota compositions of the children directly receiving the probiotic combination (LGG + Bb12) were significantly different from those of the children receiving the other intervention modes or placebo (p = 0.0012; PERMANOVA), the distinction being due to an increase in the relative abundance of Bifidobacterium animalis (P < 0.00010; ANCOM-BC), and the order Lactobacillales (P = 0.020; ANCOM-BC).

Conclusion

The connection between aberrant primary gut microbiota and a heightened risk of infectious and non-communicable diseases invites effective microbiota modulation. We show that the direct, early, and brief probiotic intervention of LGG + Bb12 109 CFU each, is sufficient to modulate the gut microbiota of the preterm neonate.

Impact

Preterm children have a higher risk of several health problems partly due to their aberrant gut microbiota.

More research is needed to find a safe probiotic intervention to modify the gut microbiota of preterm children. The maternal administration route via breast milk might be safer for the newborn.

In our study, the early and direct administration of the probiotic combination Lactobacillus rhamnosus GG with Bifidobacterium lactis Bb-12 increased the proportion of bifidobacteria in the preterm children’s gut at the age of 7 days, but the maternal administration route was not as effective.
Necrocide 1 mediates necrotic cell death and immunogenic response in human cancer cells
Authors: Zhang Jing , Trojel-Hansen Christina , Wang Jianghuang , Zhang Zili , Wang Xing , Qiao Yuhui , Jiao Huike , Michaud Mickaël , Kepp Oliver , Jäättelä Marja , Kroemer Guido , Zhong Qing
Published: April 2023

Many anticancer agents induce apoptosis, mitotic catastrophe or cellular senescence. Here, we report the functional characterization of an experimental inducer of tumor necrosis factor (TNF)-independent necrosis, necrocide-1 (NC1). NC1 (but not its stereoisomer) killed a panel of human cancer cells (but not normal cells) at nanomolar concentrations and with a non-apoptotic, necrotic morphotype, both in vitro and in vivo. NC1-induced killing was not inhibited by caspase blockers, anti-apoptotic BCL2 overexpression or TNFα neutralization, suggesting that NC1 elicits a bona fide necrotic pathway. However, pharmacological or genetic inhibition of necroptosis, pyroptosis and ferroptosis failed to block NC1-mediated cell death. Instead, NC1 elicited reactive oxygen species (ROS) production by mitochondria, and elimination of mitochondrial DNA, quenching of mitochondrial ROS, as well as blockade of mitochondrial permeability transition with cyclosporine A, interfered with NC1-induced cell death. NC1 induced hallmarks of immunogenic cell death incurring calreticulin (CALR) exposure, ATP secretion and high mobility group box 1 (HMGB1) release. Taken together, these data identify a previously uncharacterized signaling cascade leading to an immunogenic variant of mitochondrion-regulated necrosis, supporting the notion that eliciting regulated necrosis may constitute a valid approach for anticancer therapy.
Derepression may masquerade as activation in ligand-gated ion channels
Authors: Tessier Christian J. G. , Emlaw Johnathon R. , Sturgeon Raymond M. , daCosta Corrie J. B.
Published: April 2023

Agonists are ligands that bind to receptors and activate them. In the case of ligand-gated ion channels, such as the muscle-type nicotinic acetylcholine receptor, mechanisms of agonist activation have been studied for decades. Taking advantage of a reconstructed ancestral muscle-type β-subunit that forms spontaneously activating homopentamers, here we show that incorporation of human muscle-type α-subunits appears to repress spontaneous activity, and furthermore that the presence of agonist relieves this apparent α-subunit-dependent repression. Our results demonstrate that rather than provoking channel activation/opening, agonists may instead ‘inhibit the inhibition’ of intrinsic spontaneous activity. Thus, agonist activation may be the apparent manifestation of agonist-induced derepression. These results provide insight into intermediate states that precede channel opening and have implications for the interpretation of agonism in ligand-gated ion channels.
Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia
Authors: Wang Hanlin , Luo Guanghao , Hu Xiaobei , Xu Gaoya , Wang Tao , Liu Minmin , Qiu Xiaohui , Li Jianan , Fu Jingfeng , Feng Bo , Tu Yutong , Kan Weijuan , Wang Chang , Xu Ran , Zhou Yubo , Yang Jianmin , Li Jia
Published: April 2023

The outcomes of FLT3-ITD acute myeloid leukaemia (AML) have been improved since the approval of FLT3 inhibitors (FLT3i). However, approximately 30-50% of patients exhibit primary resistance (PR) to FLT3i with poorly defined mechanisms, posing a pressing clinical unmet need. Here, we identify C/EBPα activation as a top PR feature by analyzing data from primary AML patient samples in Vizome. C/EBPα activation limit FLT3i efficacy, while its inactivation synergistically enhances FLT3i action in cellular and female animal models. We then perform an in silico screen and identify that guanfacine, an antihypertensive medication, mimics C/EBPα inactivation. Furthermore, guanfacine exerts a synergistic effect with FLT3i in vitro and in vivo. Finally, we ascertain the role of C/EBPα activation in PR in an independent cohort of FLT3-ITD patients. These findings highlight C/EBPα activation as a targetable PR mechanism and support clinical studies aimed at testing the combination of guanfacine with FLT3i in overcoming PR and enhancing the efficacy of FLT3i therapy.
Extended DNA threading through a dual-engine motor module of the activating signal co-integrator 1 complex
Authors: Jia Junqiao , Hilal Tarek , Bohnsack Katherine E. , Chernev Aleksandar , Tsao Ning , Bethmann Juliane , Arumugam Aruna , Parmely Lane , Holton Nicole , Loll Bernhard , Mosammaparast Nima , Bohnsack Markus T. , Urlaub Henning , Wahl Markus C.
Published: April 2023

Activating signal co-integrator 1 complex (ASCC) subunit 3 (ASCC3) supports diverse genome maintenance and gene expression processes, and contains tandem Ski2-like NTPase/helicase cassettes crucial for these functions. Presently, the molecular mechanisms underlying ASCC3 helicase activity and regulation remain unresolved. We present cryogenic electron microscopy, DNA-protein cross-linking/mass spectrometry as well as in vitro and cellular functional analyses of the ASCC3-TRIP4 sub-module of ASCC. Unlike the related spliceosomal SNRNP200 RNA helicase, ASCC3 can thread substrates through both helicase cassettes. TRIP4 docks on ASCC3 via a zinc finger domain and stimulates the helicase by positioning an ASC-1 homology domain next to the C-terminal helicase cassette of ASCC3, likely supporting substrate engagement and assisting the DNA exit. TRIP4 binds ASCC3 mutually exclusively with the DNA/RNA dealkylase, ALKBH3, directing ASCC3 for specific processes. Our findings define ASCC3-TRIP4 as a tunable motor module of ASCC that encompasses two cooperating NTPase/helicase units functionally expanded by TRIP4.
Structure of the heterotrimeric membrane protein complex FtsB-FtsL-FtsQ of the bacterial divisome
Authors: Nguyen Hong Thuy Vy , Chen Xiaorui , Parada Claudia , Luo An-Chi , Shih Orion , Jeng U-Ser , Huang Chia-Ying , Shih Yu-Ling , Ma Che
Published: April 2023

The synthesis of the cell-wall peptidoglycan during bacterial cell division is mediated by a multiprotein machine, called the divisome. The essential membrane protein complex of FtsB, FtsL and FtsQ (FtsBLQ) is at the heart of the divisome assembly cascade in Escherichia coli. This complex regulates the transglycosylation and transpeptidation activities of the FtsW-FtsI complex and PBP1b via coordination with FtsN, the trigger for the onset of constriction. Yet the underlying mechanism of FtsBLQ-mediated regulation is largely unknown. Here, we report the full-length structure of the heterotrimeric FtsBLQ complex, which reveals a V-shaped architecture in a tilted orientation. Such a conformation could be strengthened by the transmembrane and the coiled-coil domains of the FtsBL heterodimer, as well as an extended β-sheet of the C-terminal interaction site involving all three proteins. This trimeric structure may also facilitate interactions with other divisome proteins in an allosteric manner. These results lead us to propose a structure-based model that delineates the mechanism of the regulation of peptidoglycan synthases by the FtsBLQ complex.
Limited induction of polyfunctional lung-resident memory T cells against SARS-CoV-2 by mRNA vaccination compared to infection
Authors: Pieren Daan K. J. , Kuguel Sebastián G. , Rosado Joel , Robles Alba G. , Rey-Cano Joan , Mancebo Cristina , Esperalba Juliana , Falcó Vicenç , Buzón María J. , Genescà Meritxell
Published: April 2023

Resident memory T cells (TRM) present at the respiratory tract may be essential to enhance early SARS-CoV-2 viral clearance, thus limiting viral infection and disease. While long-term antigen-specific TRM are detectable beyond 11 months in the lung of convalescent COVID-19 patients, it is unknown if mRNA vaccination encoding for the SARS-CoV-2 S-protein can induce this frontline protection. Here we show that the frequency of CD4+ T cells secreting IFNγ in response to S-peptides is variable but overall similar in the lung of mRNA-vaccinated patients compared to convalescent-infected patients. However, in vaccinated patients, lung responses present less frequently a TRM phenotype compared to convalescent infected individuals and polyfunctional CD107a+ IFNγ+ TRM are virtually absent in vaccinated patients. These data indicate that mRNA vaccination induces specific T cell responses to SARS-CoV-2 in the lung parenchyma, although to a limited extend. It remains to be determined whether these vaccine-induced responses contribute to overall COVID-19 control.
Realizing high-capacity all-solid-state lithium-sulfur batteries using a low-density inorganic solid-state electrolyte
Authors: Wang Daiwei , Jhang Li-Ji , Kou Rong , Liao Meng , Zheng Shiyao , Jiang Heng , Shi Pei , Li Guo-Xing , Meng Kui , Wang Donghai
Published: April 2023

Lithium-sulfur all-solid-state batteries using inorganic solid-state electrolytes are considered promising electrochemical energy storage technologies. However, developing positive electrodes with high sulfur content, adequate sulfur utilization, and high mass loading is challenging. Here, to address these concerns, we propose using a liquid-phase-synthesized Li3PS4-2LiBH4 glass-ceramic solid electrolyte with a low density (1.491 g cm−3), small primary particle size (~500 nm) and bulk ionic conductivity of 6.0 mS cm−1 at 25 °C for fabricating lithium-sulfur all-solid-state batteries. When tested in a Swagelok cell configuration with a Li-In negative electrode and a 60 wt% S positive electrode applying an average stack pressure of ~55 MPa, the all-solid-state battery delivered a high discharge capacity of about 1144.6 mAh g−1 at 167.5 mA g−1 and 60 °C. We further demonstrate that the use of the low-density solid electrolyte increases the electrolyte volume ratio in the cathode, reduces inactive bulky sulfur, and improves the content uniformity of the sulfur-based positive electrode, thus providing sufficient ion conduction pathways for battery performance improvement.
Algal cell bionics as a step towards photosynthesis-independent hydrogen production
Authors: Xu Zhijun , Qi Jiarui , Wang Shengliang , Liu Xiaoman , Li Mei , Mann Stephen , Huang Xin
Published: April 2023

The engineering and modulation of living micro-organisms is a key challenge in green bio-manufacturing for the development of sustainable and carbon-neutral energy technologies. Here, we develop a cellular bionic approach in which living algal cells are interfaced with an ultra-thin shell of a conductive polymer along with a calcium carbonate exoskeleton to produce a discrete cellular micro-niche capable of sustained photosynthetic and photosynthetic-independent hydrogen production. The surface-augmented algal cells induce oxygen depletion, conduct photo-induced extracellular electrons, and provide structural and chemical stability that collectively give rise to localized hypoxic conditions and concomitant hydrogenase activity under daylight in air. We show that assembly of the living cellular micro-niche opens a direct extracellular photoelectron pathway to hydrogenase resulting in photosynthesis-independent hydrogen evolution for 200 d. In addition, surface-conductive dead algal cells continue to produce hydrogen for up to 8 d due to their structural stability and retention of functional hydrogenases. Overall, the integration of artificial biological hydrogen production pathways and natural photosynthesis in surface-augmented algal cells provides a cellular bionic approach to enhanced green hydrogen production under environmentally benign conditions and could pave the way to new opportunities in sustainable energy production.
Ruthenium-cobalt single atom alloy for CO photo-hydrogenation to liquid fuels at ambient pressures
Authors: Zhao Jiaqi , Liu Jinjia , Li Zhenhua , Wang Kaiwen , Shi Run , Wang Pu , Wang Qing , Waterhouse Geoffrey I. N. , Wen Xiaodong , Zhang Tierui
Published: April 2023

Photothermal Fischer-Tropsch synthesis represents a promising strategy for converting carbon monoxide into value-added chemicals. High pressures (2-5 MPa) are typically required for efficient C-C coupling reactions and the production of C5+ liquid fuels. Herein, we report a ruthenium-cobalt single atom alloy (Ru1Co-SAA) catalyst derived from a layered-double-hydroxide nanosheet precursor. Under UV-Vis irradiation (1.80 W cm−2), Ru1Co-SAA heats to 200 °C and photo-hydrogenates CO to C5+ liquid fuels at ambient pressures (0.1-0.5 MPa). Single atom Ru sites dramatically enhance the dissociative adsorption of CO, whilst promoting C-C coupling reactions and suppressing over-hydrogenation of CHx* intermediates, resulting in a CO photo-hydrogenation turnover frequency of 0.114 s−1 with 75.8% C5+ selectivity. Owing to the local Ru-Co coordination, highly unsaturated intermediates are generated during C-C coupling reactions, thereby improving the probability of carbon chain growth into C5+ liquid fuels. The findings open new vistas towards C5+ liquid fuels under sunlight at mild pressures.
An emerging generation of endocrine therapies in breast cancer: a clinical perspective
Authors: Patel Rima , Klein Paula , Tiersten Amy , Sparano Joseph A.
Published: April 2023

Anti-estrogen therapy is a key component of the treatment of both early and advanced-stage hormone receptor (HR)-positive breast cancer. This review discusses the recent emergence of several anti-estrogen therapies, some of which were designed to overcome common mechanisms of endocrine resistance. The new generation of drugs includes selective estrogen receptor modulators (SERMs), orally administered selective estrogen receptor degraders (SERDs), as well as more unique agents such as complete estrogen receptor antagonists (CERANs), proteolysis targeting chimeric (PROTACs), and selective estrogen receptor covalent antagonists (SERCAs). These drugs are at various stages of development and are being evaluated in both early and metastatic settings. We discuss the efficacy, toxicity profile, and completed and ongoing clinical trials for each drug and highlight key differences in their activity and study population that have ultimately influenced their advancement.
A large-scale repository of spoken narratives in French, German and Spanish from Cantonese-speaking learners
Authors: Kang Xin , Yip Virginia , Matthews Stephen , Wong Patrick C. M.
Published: April 2023

Interdisciplinary research on foreign language learning has important implications for learning and education. In this paper, we present the Repository of Third Language (L3) Spoken Narratives from Modern Language Learners in Hong Kong (L3HK Repository). This database contains 906 audio recordings and annotated transcripts of spoken narratives in French, German, and Spanish that were elicited from Cantonese-speaking (L1) young adults using a wordless picture book, “Frog, Where Are You?”. All participants spoke English as the second language (L2) and learned the target language as a third language (L3). We collected their demographic information, answers to a motivation questionnaire, parental socioeconomic status, and music background. Furthermore, for a subset of participants, we collected their L1 and L2 proficiency scores and additional experimental data on working memory and music perception. This database is valuable for examining cross-sectional changes in foreign language learning. The extensive data on phenotypes provide opportunities to explore learner-internal and learner-external factors in foreign language learning outcomes. These data may also be helpful for those who work on speech recognition.
Extensive 3D mapping of dislocation structures in bulk aluminum
Authors: Yildirim Can , Poulsen Henning F. , Winther Grethe , Detlefs Carsten , Huang Pin H. , Dresselhaus-Marais Leora E.
Published: April 2023

Thermomechanical processing such as annealing is one of the main methods to tailor the mechanical properties of materials, however, much is unknown about the reorganization of dislocation structures deep inside macroscopic crystals that give rise to those changes. Here, we demonstrate the self-organization of dislocation structures upon high-temperature annealing in a mm-sized single crystal of aluminum. We map a large embedded 3D volume ($$100\times 300\times 300$$

100
×
300
×
300

$$\upmu$$
μ
m$$^3$$

3

) of dislocation structures using dark field X-ray microscopy (DFXM), a diffraction-based imaging technique. Over the wide field of view, DFXM’s high angular resolution allows us to identify subgrains, separated by dislocation boundaries, which we identify and characterize down to the single-dislocation level using computer-vision methods. We demonstrate how even after long annealing times at high temperatures, the remaining low density of dislocations still pack into well-defined, straight dislocation boundaries (DBs) that lie on specific crystallographic planes. In contrast to conventional grain growth models, our results show that the dihedral angles at the triple junctions are not the predicted 120$$^{\circ }$$

∘

, suggesting additional complexities in the boundary stabilization mechanisms. Mapping the local misorientation and lattice strain around these boundaries shows that the observed strain is shear, imparting an average misorientation around the DB of $$\approx$$
≈
0.003 to 0.006$$^{\circ }$$

∘

.
The unconditioned fear response in dystrophin-deficient mice is associated with adrenal and vascular function
Authors: Lindsay Angus , Russell Aaron P.
Published: April 2023

Loss of function mutations in the gene encoding dystrophin elicits a hypersensitive fear response in mice and humans. In the dystrophin-deficientmdxmouse, this behaviour is partially protected by oestrogen, but the mechanistic basis for this protection is unknown. Here, we show that femalemdxmice remain normotensive during restraint stress compared to a hypotensive and hypertensive response in malemdxand male/female wildtype mice, respectively. Partial dystrophin expression in femalemdxmice (heterozygous) also elicited a hypertensive response. Ovariectomized (OVX) femalemdxmice were used to explain the normotensive response to stress. OVX lowered skeletal muscle mass and lowered the adrenal mass and zona glomerulosa area (aldosterone synthesis) in femalemdxmice. During a restraint stress, OVX dampened aldosterone synthesis and lowered the corticosterone:11-dehydrocorticosterone. All OVX-induced changes were restored with replacement of oestradiol, except that oestradiol lowered the zona fasciculata area of the adrenal gland, dampened corticosterone synthesis but increased cortisol synthesis. These data suggest that oestrogen partially attenuates the unconditioned fear response inmdxmice via adrenal and vascular function. It also suggests that partial dystrophin restoration in a dystrophin-deficient vertebrate is an effective approach to develop an appropriate hypertensive response to stress.
Discrimination of the chemotherapy resistance status of human leukemia and glioblastoma cell lines by MALDI-TOF-MS profiling
Authors: Ledesma Martín , Poodts Daniela , Amoia Sofía , Hajos Silvia , Fundia Ariela , Vay Carlos , Pibuel Matías , Lompardía Silvina
Published: April 2023

Chemotherapy mistreatment is partially due to a lack of rapid and reliable tools to discriminate between sensitive and resistant phenotypes. In many cases, the resistance mechanism is not fully understood, contributing to the diagnostic tools' absence. This work aims to determine the capacity of MALDI-TOF-MS profiling to discriminate between chemotherapy-resistant and sensitive phenotypes in leukemia and glioblastoma cells. A multivariate analysis of two therapy-resistant leukemia cell lines (Ki562 and Kv562) and two TMZ-resistant glioblastoma cell lines (U251-R and LN229-R) and their sensitive counterparts was performed. In this work, we first show MALDI-TOF-MS patterns analysis ability to differentiate these cancer cell lines by their chemotherapy-resistant status. We present a rapid and inexpensive tool that would guide and complement the therapeutic decision.
High p doped and robust band structure in Mg-doped hexagonal boron nitride
Authors: Khalil Lama , Ernandes Cyrine , Avila José , Rousseau Adrien , Dudin Pavel , Zhigadlo Nikolai D. , Cassabois Guillaume , Gil Bernard , Oehler Fabrice , Chaste Julien , Ouerghi Abdelkarim
Published: April 2023

In two dimensional materials, substitutional doping during growth can be used to alter the electronic properties.
A comparative study on the allergenic potential of β-lactoglobulin conjugated to glucose, caffeic acid and caffeoyl glucopyranose
Authors: Wang Yang , Zhang Kai , Mao Yi-ying , Shao Yan-hong , Liu Jun , Tu Zong-cai
Published: April 2023

Covalent modification of β-lactoglobulin by 6-O-(E)-caffeoylglucopyranose changed the structure, which reduced the allergic risk of BALB/c mice by the changes in Th1/Th2 balance and SCFA levels produced by the allergy-related gut flora.
Broadband photoresponse in plasmon-enhanced Ga-doped ZnO
Authors: Yang Manli , Weng Xiaoliang , Iqbal Muhammad Ahsan , Kang Chenxu , Zhang Su-Yun , Zeng Yu-Jia
Published: April 2023

We develop Ga-doped ZnO (GZO) photodetectors with localized surface plasmon resonance (LSPR) properties.
Large tunneling magnetoresistance in spin-filtering 1T-MnSe2/h-BN van der Waals magnetic tunnel junction
Authors: Chen Zhao , Liu Xiaofeng , Li Xingxing , Gao Pengfei , Li ZhongJun , Zhu Weiduo , Wang Haidi , Li Xiangyang
Published: April 2023

We propose a two-dimensional magnetic tunnel junction of 1T-MnSe2/h-BN/1T-MnSe2/h-BN/1T-MnSe2with efficient electrical writing, reliable reading operations and high potential to work at room temperature.
A luminescent Cu4 cluster film grown by electrospray deposition: a nitroaromatic vapour sensor
Authors: Jana Arijit , Spoorthi B. K. , Nair Akhil S. , Nagar Ankit , Pathak Biswarup , Base Tomas , Pradeep Thalappil
Published: April 2023

We present the fabrication of a film of a carborane-thiol-protected tetranuclear copper cluster using the ambient electrospray deposition (ESD) technique. This orange luminescent film functions as a selective and reversible nitroaromatic vapour sensor.