bluuebunny/crossref_metadata_2025 huggingface dataset:
On the rising and sinking motion of bouncing oil drops in strongly stratified liquids
Authors: Meijer Jochem G. , Li Yanshen , Diddens Christian , Lohse Detlef
Published: June 2023

When an immiscible oil drop is immersed in a stably stratified ethanol–water mixture, the Marangoni flow on the surface of the drop can experience an oscillatory instability, so that the drop undergoes a transition from levitating to bouncing. The onset of the instability and its mechanisms have been studied previously (Li et al., Phys. Rev. Lett., vol. 126, 2021, 124502; Li et al., J. Fluid Mech., vol. 932, 2022, A11), yet the bouncing motion of the drop itself, which is a completely different problem, has not yet been investigated. Here we study how the bouncing characteristics (jumping height, rising and sinking time) depend on the control parameters (drop radius, stratification strength, drop viscosity). We first record experimentally the bouncing trajectories of drops of different viscosities in different stratifications. Then a simplified dynamical analysis is performed to get the scaling relations of the jumping height and the rising and sinking times. The rising and sinking time scales are found to depend on the drag coefficient

$C_D^S$

of the drop in the stratified liquid, which is determined empirically for the current parameter space (Zhang et al., J. Fluid Mech., vol. 875, 2019, 622–656). For low-viscosity (5 cSt) oil drops, the results on the drag coefficient match those from the literature (Yick et al., J. Fluid Mech., vol. 632, 2009, pp. 49–68; Candelier et al., J. Fluid Mech., vol. 749, 2014, pp. 184–200). For high-viscosity (100 cSt) oil drops, the parameter space had not been explored and the drag coefficients are not readily available. Numerical simulations are therefore performed to provide external verification for the drag coefficients, which well match with the experimental results.
BIG IN REVERSE MATHEMATICS: THE UNCOUNTABILITY OF THE REALS
Authors: SANDERS SAM
Published: June 2023

The uncountability of$\mathbb {R}$is one of its most basic properties, known far outside of mathematics. Cantor’s 1874 proof of the uncountability of$\mathbb {R}$even appears in the very first paper on set theory, i.e., a historical milestone. In this paper, we study the uncountability of${\mathbb R}$in Kohlenbach’shigher-orderReverse Mathematics (RM for short), in the guise of the following principle:$$\begin{align*}\mathit{for \ a \ countable \ set } \ A\subset \mathbb{R}, \mathit{\ there \ exists } \ y\in \mathbb{R}\setminus A. \end{align*}$$

An important conceptual observation is that the usual definition of countable set—based on injections or bijections to${\mathbb N}$—does not seem suitable for the RM-study of mainstream mathematics; we also propose a suitable (equivalent over strong systems) alternative definition of countable set, namelyunion over${\mathbb N}$of finite sets; the latter is known from the literature and closer to how countable sets occur ‘in the wild’. We identify a considerable number of theorems that are equivalent to the centred theorem based on our alternative definition. Perhaps surprisingly, our equivalent theorems involve most basic properties of the Riemann integral, regulated or bounded variation functions, Blumberg’s theorem, and Volterra’s early work circa 1881. Our equivalences are alsorobust, promoting the uncountability of${\mathbb R}$to the status of ‘big’ system in RM.
COMPLETE BIPARTITE PARTITION RELATIONS IN COHEN EXTENSIONS
Authors: UHRIK DÁVID
Published: June 2023

We investigate the effect of adding

$\omega _2$

Cohen reals on graphs on

$\omega _2$

, in particular we show that

$\omega _2 \to (\omega _2, \omega : \omega )^2$

holds after forcing with

$\mathsf {Add}(\omega , \omega _2)$

in a model of

$\mathsf {CH}$

. We also prove that this result is in a certain sense optimal as

$\mathsf {Add}(\omega , \omega _2)$

forces that

$\omega _2 \not \to (\omega _2, \omega : \omega _1)^2$

.
Maya Pilgrimage, Migration, and Community Connectivity at Ritual Landscapes at Mensabak, Chiapas, Mexico
Authors: Palka Joel W.
Published: June 2023

Anthropologists have demonstrated that having information about new settlements is crucial for drawing migrants. Pilgrimage to ritual landscapes and their shrines allows people, including Maya societies, to explore places where they can settle. They then establish or augment settlements around the landscape shrines, which explains the locations and growth of some centers. Migrants continue to make pilgrimages to shrines, such as sacred mountains, near their receiving settlements to enhance community cohesion through ritual contact with spiritual forces. In this article, I show that pilgrimage is an important element in the establishment of select migrant settlements and their community identity. I focus on Maya and Mesoamerican cultures, particularly at Mensabak in Chiapas, Mexico, and on supporting archaeological, historical, and ethnographic information. I conclude that Maya perceptions of movement, connectivity, and transformation in their world are linked to pilgrimage, migration, and community formation. Importantly, pilgrimage provides a religious variable, in addition to better-known economic, political, or demographic factors, to consider in migration.
Erythrocyte membrane n-3 PUFA are inversely associated with breast cancer risk among Chinese women
Authors: Zhang Zhuo-Lin , Ho Suzanne C , Shi Dan-Dan , Zhan Xiao-Xia , Wu Qi-Xin , Xu Lei , Zhang Cai-Xia
Published: June 2023

The relationship between erythrocyte membrane n-3 PUFA and breast cancer risk is controversial. We aimed to examine the associations of erythrocyte membrane n-3 PUFA with odds of breast cancer among Chinese women by using a relatively large sample size. A case–control study was conducted including 853 newly diagnosed, histologically confirmed breast cancer cases and 892 frequency-matched controls (5-year interval). Erythrocyte membrane n-3 PUFA were measured by GC. Logistic regression and restricted cubic spline were used to quantify the association between erythrocyte membrane n-3 PUFA and odds of breast cancer. Erythrocyte membrane α-linolenic acid (ALA), docosapentaenoic acid (DPA) and total n-3 PUFA were inversely and non-linearly associated with odds of breast cancer. The OR values (95 % CI), comparing the highest with the lowest quartile (Q), were 0·57 (0·43, 0·76), 0·43 (0·32, 0·58) and 0·36 (0·27, 0·49) for ALA, DPA and total n-3 PUFA, respectively. Erythrocyte membrane EPA and DHA were linearly and inversely associated with odds of breast cancer ((EPA: ORQ4 v. Q1 (95 % CI) = 0·59 (0·45, 0·79); DHA: ORQ4 v. Q1 (95 % CI) = 0·50 (0·37, 0·67)). The inverse associations were observed between ALA and odds of breast cancer in postmenopausal women, and between DHA and oestrogen receptor+ breast cancer. This study showed that erythrocyte membrane total and individual n-3 PUFA were inversely associated with odds of breast cancer. Other factors, such as menopause and hormone receptor status, may warrant further investigation when examining the association between n-3 PUFA and odds of breast cancer.
Language at the Limits of the Human: Deceit, Invention, and the Specter of the Unshared Symbol
Authors: Handman Courtney
Published: June 2023

Both the theories coming out of the linguistic turn and those running away from it have placed special emphasis on human language (or human symbolic thinking) as a matter of convention and shared meanings. Yet there are other histories that link language and humanness through invention, deceit, and secrecy rather than through convention and publicness. These alternate models have been used as diagnostic of humanness in a range of contexts, from the colonial past into the technologized present. I examine here the ways in which the unshared, non-public symbol has stood at the center of two disparate contexts in which the humanness of speakers of novel languages are put in question. The first case examines the ways in which Christian missionaries started to see Tok Pisin, a novel pidginized language spoken by indentured laborers in colonial Papua New Guinea, as a possible language of evangelism when it became associated with deceit and moral dissolution. The second case examines a 2017 moral panic in the United States about two chatbots that were reported to have invented their own language and then used it to lie to one another. In contrast to the first case, one of the ways that bots get figured as beyond-human is in the fear that there is no way to impose a moral order, no colonial evangelism that could be used to encompass them. By taking on the symbolic while withholding public meanings, the speakers of these unshared symbols sit at the boundaries of humanness.
From an existential-humanistic perspective: examining factors contributing to purpose in life among artistically inclined individuals from middle to later life
Authors: Chou Ying-Yi Patricia
Published: June 2023

Purpose in life has been found to decline from middle to later life in several ageing studies. Because the decline has negative impacts on health-related outcomes, it is important to identify factors contributing to purpose in life to enhance wellbeing among the ageing population. This study first examined the role of subjective social economic status (SSES) in the relationship between age and purpose in life. Subsequent analyses estimated whether the construct Artistic Creativity as a Source for Meaning in Life (ACASMIL) played a role in cultivating purpose in life among ageing individuals. Moreover, the analyses determined whether this effect was strengthened by creative self-concept (i.e. self-conviction about personal identity and self-efficacy in the global domain of creativity). Results from a sample of 224 individuals from middle to third age (mean age = 54.08, standard deviation = 10.08, range = 40–84) revealed that the relationship between age and purpose in life was only positive among those with relatively high SSES, controlling for gender and country of residence. Controlling for gender, country of residence, age and SSES, it was found that ACASMIL did not play a mediator role. Moreover, creative self-concept played a moderator role in the relationship between artistic creativity and ACASMIL. However, this moderation effect of creative self-concept was negative. Implications and suggestions for future directions are discussed.
Social competence as a predictor of adult outcomes in autism spectrum disorder
Authors: Clarke Elaine B. , Lord Catherine
Published: June 2023

There is a wealth of literature characterizing social difficulties in autism spectrum disorder (ASD). However, little work has replicated longitudinal findings from typical development that adolescent social competence predicts positive adult outcomes in ASD. The current study examined social competence trajectories from 2 to 26 and the utility of three social competence measures collected in adolescence in predicting work, residential status, friendship, and romantic outcomes in a longitudinal cohort (n = 253) of ASD. Using group-based trajectory modeling, we identified two patterns of social competence development: a low trajectory characterized by slow linear gains throughout childhood and plateauing in adulthood, and a high trajectory characterized by steeper linear gains in childhood followed by decline in adulthood. Regression models indicated one social competence measure, Vineland Social-AE scores, significantly predicted employment, residential status, and friendships in adulthood. One other social competence measure, SSQ total scores, also significantly predicted friendship in adulthood. Only nonverbal IQ at 9 predicted the likelihood of having ever had a romantic relationship. These findings highlight the role of social competence in both atypical and typical development and suggest the social impairments associated with ASD do not necessarily impact all realms of social functioning equally.
Massive bilateral pulmonary embolism in a child
Authors: Rodriguez Quero Saby , Leon Wyss Juan Ricardo , Baez Chalas Adabeyda
Published: June 2023

We describe a rare case of acute pulmonary artery thromboembolism in a 17-year-old male patient who presented to our emergency department following a syncopal episode. A chest radiograph showed a convex pulmonic cone and an increased cardiothoracic index, and two-dimensional echocardiogram suggested near-occlusion of both pulmonary arterial branches. Multi-slice pulmonary angio-tomography revealed massive thrombosis of the pulmonary artery. He was treated with systemic anticoagulation and subsequently required surgical thrombectomy, with favourable early outcome. Although the cause of the thromboembolism remains unproven, we discuss possible etiologies.
Characterization of the complete chloroplast genome ofVitex bicolorWilld. and its comparative analyses with other species belonging to theVitex trifoliacomplex
Authors: Gentallan Renerio P. , Quiñones Kristine Joyce O. , Bartolome Michael Cedric B. , Madayag Roselle E. , Altoveros Nestor C. , Endonela Leah E. , Lalusin Antonio G. , Reyes Melquiades Emmanuel C. , Ocampo Eureka Teresa M. , Timog Emmanuel Bonifacio S. , Borromeo Teresita H.
Published: June 2023

V. bicolor,V. trifolias. str. andV. rotundifoliaare part of a species complex that has recorded medicinal use in the Philippines. We assembled the first chloroplast genome ofV. bicolorthrough next-generation sequencing and compared this to earlier established chloroplast genomes ofV. trifolias. str. andV. rotundifoliato provide additional insights into their genotypic differences. To ensure the continued utility of the research outputs in case of future taxonomic revisions, we characterized the morphology of PBN 2018-674, the reference germplasm utilized to generate the plastome. The complete chloroplast genome sequence ofV. bicolorwas 154,460 bp long with 131 coding genes comprising 87 mRNA genes, 36 tRNA genes and 8 rRNA genes. Using a separate accession from a different type locality, an identical chloroplast genome was equally established, indicating its conserved nature. When compared toV. trifolias. str. andV. rotundifolia, slight variations were observed in genome features between these species; however, single nucleotide polymorphisms were exhibited in 13 protein-coding genes that often have a conserved nature. A phylogenetic analysis of the assembled genome, together with 12 other Lamiaceae species, exhibited high bootstrap support (>88%) within the species complex, and associatedV. trifoliaas the closest relative ofV. bicolor. The identified variations in the plastomes can be utilized as markers that could distinguish the three closely related genotypes which can help the Philippine herbal industry provide a more stable source of quality herbal medicines.
Slotted vertical wall for decoupling and beam tilt correction
Authors: Wang Yiying , Zhang Shengfei , Wang Bo , Zhang Hongxin , Jiang Yannan , Pan Wanghua , Kishk Ahmed A.
Published: June 2023

An intra-band pattern-corrected decoupling vertical conducting wall is realized by dielectric substrate with conductor cladding on both side wall between two tightly spaced H-plane microstrip patches with λ0/20 edge-to-edge spacing. The wall is grounded and two symmetrical slots are etched on the vertical substrate. The measured results agree with the simulations, showing that the slotted vertical wall reduces the mutual coupling within the bandwidth to −30 dB and corrects the radiation beam tilt to be within −4.5° to 3° from the broadside direction. A gain reduction of 0.6 dB is observed compared to the gain without the slotted decoupling wall.
Preemergence herbicide premixes reduce the risk of soil residual weed control failure in corn
Authors: Silva Tatiane Severo , Arneson Nicholas John , DeWerff Ryan P. , Smith Daniel H , Silva Daniel Valadão , Werle Rodrigo
Published: June 2023

Widespread occurrence of herbicide-resistant weeds and more variable weather conditions across the United States has made weed control in many crops more challenging. Preemergence (PRE) herbicides with soil residual activity have resurged as the foundation for early season weed control in many crops. Field experiments were conducted in Janesville and Lancaster, Wisconsin, in 2021 and 2022 (4 site-years) to evaluate the weed control efficacy of solo (single site of action [SOA]) and premix (two or more SOAs) PRE herbicides in conventional tillage corn. Treatments consisted of 18 PRE herbicides plus a nontreated check. At the Janesville-2021 site, S-metolachlor + bicyclopyrone + mesotrione, atrazine + S-metolachlor + bicyclopyrone + mesotrione, and clopyralid + acetochlor + mesotrione provided >72% giant ragweed control. At the Janesville-2022 site, none of the PRE herbicides evaluated provided >70% giant ragweed control due to the high giant ragweed density and the lack of timely rainfall. At the Lancaster-2021 site, atrazine, dicamba, and flumetsulam + clopyralid provided <45% waterhemp control, but the remaining treatments provided >90% control. At the Lancaster-2022 site, the efficacy of some PRE herbicides was reduced due to the high waterhemp density; however, most herbicides provided >75% control. At the Lancaster-2021 and Lancaster-2022 sites, only dicamba and S-metolachlor did not provide >75% common lambsquarters control. Group 15 PRE herbicides provided >75% control of giant foxtail. Across weed species, PRE herbicides with two (78%) and three (81%) SOAs provided greater weed control than PRE herbicides with a single SOA (68%), indicating that at least two SOA herbicides applied PRE result in better early season weed control. The efficacy of the PRE herbicide treatments evaluated herein varied according to the soil seedbank weed community composition and environmental conditions (i.e., rainfall following application), but the premixes were a more reliable option to improve early season weed control in conventional tillage corn.
Developing a New Tool for International Youth Programs
Authors: Omoeva Carina , Menezes Cunha Nina , Kyllonen Patrick , Gates Sarah , Martinez Andres , Burke Holly M.
Published: June 2023

Abstract: We developed and evaluated the YouthPower Action Youth Soft Skills Assessment (YAYSSA), a self-report soft skills measure. The YAYSSA targets 15- to 19-year-old youth in lower resource environments. In Study 1, we identified 16 key constructs based on a review of those associated with positive youth outcomes in sexual and reproductive health, violence prevention, and workforce success. We adapted promising items measuring those constructs from existing and openly available tools. We conducted cognitive interviews with 50 youth from six schools in Uganda, for wording and response formats, leading to a first draft tool. In Study 2 we administered that tool to N = 1,098 youth in 59 schools in Uganda. Confirmatory factor analyses did not support the hypothesized 16-factor structure, but exploratory factor analyses suggested a four-factor solution (Positive self-concept, Higher-order thinking skills, Social and Communication skills, and Negative self-concept). In Study 3, a revised tool was administered to Uganda youth ( N = 1,010, 59 sites). After cognitive testing with 45 youth in Guatemala, the tool was administered to youth ( N = 794; 59 sites) in Guatemala once, then 5 months later, with a mixture of retested and new participants ( N = 784; 67 sites). Factor analytic results supported the four-factor structure with 48 retained items and indicated that the instrument was reliable by internal consistency and test-retest correlations. The instrument correlated with demographic variables and outcomes in expected directions. We found evidence for measurement invariance across country, country and gender, country and socioeconomic status, and time. We discuss implications for scale validation and use in future research.
The Association of Cusp‐Aligned Arcs With Plasma in the Magnetotail Implies a Closed Magnetosphere
Authors: Milan S. E. , Mooney M. K. , Bower G. E. , Taylor M. G. G. T. , Paxton L. J. , Dandouras I. , Fazakerley A. N. , Carr C. M. , Anderson B. J. , Vines S. K.
Published: June 2023

We investigate a 15‐day period in October 2011. Auroral observations by the Special Sensor Ultraviolet Spectrographic Imager instrument onboard the Defense Meteorological Satellite Program F16, F17, and F18 spacecraft indicate that the polar regions were covered by weak cusp‐aligned arc (CAA) emissions whenever the interplanetary magnetic field (IMF) clock angle was small, |θ| < 45°, which amounted to 30% of the time. Simultaneous observations of ions and electrons in the tail by the Cluster C4 and Geotail spacecraft showed that during these intervals dense (≈1 cm−3) plasma was observed, even as far from the equatorial plane of the tail as |ZGSE| ≈ 13 RE. The ions had a pitch angle distribution peaking parallel and antiparallel to the magnetic field and the electrons had pitch angles that peaked perpendicular to the field. We interpret the counter‐streaming ions and double loss‐cone electrons as evidence that the plasma was trapped on closed field lines, and acted as a source for the CAA emission across the polar regions. This suggests that the magnetosphere was almost entirely closed during these periods. We further argue that the closure occurred as a consequence of dual‐lobe reconnection. Our finding forces a significant re‐evaluation of the magnetic topology of the magnetosphere during periods of northwards IMF.
Statistical Properties of Long‐Period Plasmapause Surface Waves From Van Allen Probes Observations
Authors: Feng Zi‐Jian , Ren Jie , Zong Qiu‐Gang , Xiang Ting‐Yan , Ai Xin‐Yu
Published: June 2023

Recent work revealed the existence of plasmapause surface waves (PSWs) with Van Allen Probes observations, which are characterized by the periodic modulations of both magnetic/electric fields and plasma densities, and suggested to be the driver of giant undulations (GUs). In this study, six years data from Van Allen Probes were used to investigate the spatial distributions and occurrence conditions of PSWs in the period of 5–30 min. PSWs are found to be mainly distributed at L = 3.5–7 and their occurrence rate is increasing with larger L shells. In the azimuth direction, the spatial distribution of PSWs exhibits an obvious dawn‐dusk asymmetry with highest occurrence rates at MLT = 15–21, which is consistent with the spatial distribution of GUs revealed in the previous study. This further demonstrates that PSWs and GUs are connected, and indicates that PSWs differ from Ps6 waves which have a similar wave period and irregular waveform but mainly concentrate in the dawnside and connect with Ω bands. PSWs preferentially occur under the condition of high solar wind velocities (VSW > 500 km/s) and high dynamic pressures (Pdyn > 5 nPa), and their occurrence rate has a negative correlation with IMF Bz, SYMH and AL. Statistical results also reveal that PSWs preferentially occur around the peak of both magnetic storms and substorms. These findings may shed new lights on the further understanding of PSWs' generation and propagation.
On the Potential for Cumulate Mantle Overturn in Mercury
Authors: Mouser Megan D. , Dygert Nicholas
Published: June 2023

Mercury has a compositionally diverse surface exhibiting geochemical terranes that represent different periods of igneous activity, suggesting diverse mantle source compositions. Mercury's juvenile mantle likely formed after fractional solidification of a magma ocean, which produced distinct mineralogical horizons with depth. To produce the diversity of observed volcanic terranes, dynamic mixing of materials from distinct mantle horizons is required. One process that could dynamically mix the juvenile cumulate pile is cumulate mantle overturn, where dense layers in shallow planetary mantles sink into deeper, less dense layers as Rayleigh‐Taylor instabilities. Gravitationally unstable density stratification is a requisite starting condition for overturn; solidification of the Mercurian magma ocean is likely to have produced such a density inversion, with a relatively dense clinopyroxene‐bearing pyroxenite layer atop lower density dunite and harzburgite layers. Sulfides are present in abundance on Mercury's surface and would be additional mantle phase(s) if they are indigenous to the planet's interior. Sulfides have variable densities; they could potentially enhance the formation of gravitational instabilities or prevent them from developing. Exploring physically reasonable mantle density and viscosity structures, we evaluate the potential for cumulate mantle overturn in Mercury and predict the possible timing, scale, and rate of overturn for plausible physical parameter combinations. Our analysis suggests that overturn is possible in Mercury's mantle within 100 Myr of magma ocean solidification, providing a mechanism for producing the mantle sources that would melt to form surface compositions on Mercury, and overturn may control the spatial scale of volcanic provinces observed on the surface today.
MEK1/2 regulate normal BCR and ABL1 tumor-suppressor functions to dictate ATO response in TKI-resistant Ph+ leukemia
Authors: Mazzera Laura , Abeltino Manuela , Lombardi Guerino , Cantoni Anna Maria , Jottini Stefano , Corradi Attilio , Ricca Micaela , Rossetti Elena , Armando Federico , Peli Angelo , Ferrari Anna , Martinelli Giovanni , Scupoli Maria Teresa , Visco Carlo , Bonifacio Massimiliano , Ripamonti Alessia , Gambacorti-Passerini Carlo , Bonati Antonio , Perris Roberto , Lunghi Paolo
Published: June 2023

Resistance to tyrosine kinase inhibitors (TKIs) remains a clinical challenge in Ph-positive variants of chronic myeloid leukemia. We provide mechanistic insights into a previously undisclosed MEK1/2/BCR::ABL1/BCR/ABL1-driven signaling loop that may determine the efficacy of arsenic trioxide (ATO) in TKI-resistant leukemic patients. We find that activated MEK1/2 assemble into a pentameric complex with BCR::ABL1, BCR and ABL1 to induce phosphorylation of BCR and BCR::ABL1 at Tyr360 and Tyr177, and ABL1, at Thr735 and Tyr412 residues thus provoking loss of BCR’s tumor-suppression functions, enhanced oncogenic activity of BCR::ABL1, cytoplasmic retention of ABL1 and consequently drug resistance. Coherently, pharmacological blockade of MEK1/2 induces dissociation of the pentameric MEK1/2/BCR::ABL1/BCR/ABL1 complex and causes a concurrent BCRY360/Y177, BCR::ABL1Y360/Y177 and cytoplasmic ABL1Y412/T735 dephosphorylation thereby provoking the rescue of the BCR’s anti-oncogenic activities, nuclear accumulation of ABL1 with tumor-suppressive functions and consequently, growth inhibition of the leukemic cells and an ATO sensitization via BCR-MYC and ABL1-p73 signaling axes activation. Additionally, the allosteric activation of nuclear ABL1 was consistently found to enhance the anti-leukemic effects of the MEK1/2 inhibitor Mirdametinib, which when combined with ATO, significantly prolonged the survival of mice bearing BCR::ABL1-T315I-induced leukemia. These findings highlight the therapeutic potential of MEK1/2-inhibitors/ATO combination for the treatment of TKI-resistant leukemia.
A force-compensated compliant MEMS-amplifier with electrostatic anti-springs
Authors: Schmitt Philip , Hoffmann Martin
Published: June 2023

In this paper, an electrostatic compliant mechanical amplifier intended for force-compensated displacement amplification in MEMS sensor applications is described. Usually, mechanical transformers that enhance a small input displacement into a large output displacement generate large forces at the input of the transformer. The microsystem proposed here allows for the reduction and compensation of the input stiffness of the amplifier and any mechanical components connected to it while providing a constant amplification ratio at the same time. The amplifying mechanism features bidirectional electrostatic anti-springs enabling the control of the stiffness by applying a constant DC voltage. The electrode design of the anti-springs and its influence on the force-displacement characteristic, the side instability and the maximal displacement are studied through analytical approaches and supported by FEA and by experiments. Based on the derived models, a compliant electromechanical amplifier is developed, featuring an amplification ratio of 50. For this amplifier the initial input stiffness of 422 N/m could be reduced to 6.8 N/m by applying a voltage of 100 V. As an additional application, we show how the amplifier can be used as a mechanical force sensor with tuneable sensitivity, where the forces at the input are transformed into large output displacements. Through experiments, we show how the sensitivity can be adjusted and increased by a factor of 25 by applying a voltage at the anti-springs.
Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine
Authors: Khanra Sourav , Reddy Preethi , Giménez-Palomo Anna , Park Chun Hui J. , Panizzutti Bruna , McCallum Madeleine , Arumugham Shyam Sundar , Umesh Shreekantiah , Debnath Monojit , Das Basudeb , Venkatasubramanian Ganesan , Ashton Melanie , Turner Alyna , Dean Olivia M. , Walder Ken , Vieta Eduard , Yatham Lakshmi N. , Pacchiarotti Isabella , Reddy Y. C. Janardhan , Goyal Nishant , Kesavan Muralidharan , Colomer Lluc , Berk Michael , Kim Jee Hyun
Published: June 2023

Bipolar disorder’s core feature is the pathological disturbances in mood, often accompanied by disrupted thinking and behavior. Its complex and heterogeneous etiology implies that a range of inherited and environmental factors are involved. This heterogeneity and poorly understood neurobiology pose significant challenges to existing drug development paradigms, resulting in scarce treatment options, especially for bipolar depression. Therefore, novel approaches are needed to discover new treatment options. In this review, we first highlight the main molecular mechanisms known to be associated with bipolar depression–mitochondrial dysfunction, inflammation and oxidative stress. We then examine the available literature for the effects of trimetazidine in said alterations. Trimetazidine was identified without a priori hypothesis using a gene-expression signature for the effects of a combination of drugs used to treat bipolar disorder and screening a library of off-patent drugs in cultured human neuronal-like cells. Trimetazidine is used to treat angina pectoris for its cytoprotective and metabolic effects (improved glucose utilization for energy production). The preclinical and clinical literature strongly support trimetazidine’s potential to treat bipolar depression, having anti-inflammatory and antioxidant properties while normalizing mitochondrial function only when it is compromised. Further, trimetazidine’s demonstrated safety and tolerability provide a strong rationale for clinical trials to test its efficacy to treat bipolar depression that could fast-track its repurposing to address such an unmet need as bipolar depression.
Appearance of tuft cells during prostate cancer progression
Authors: Vlajic Katarina , Pennington Kluger Hannah , Bie Wenjun , Merrill Bradley J. , Nonn Larisa , Kajdacsy-Balla Andre , Tyner Angela L.
Published: June 2023

Tuft cells are chemosensory epithelial cells that increase in number following infection or injury to robustly activate the innate immune response to alleviate or promote disease. Recent studies of castration resistant prostate cancer and its subtype, neuroendocrine prostate cancer, revealed Pou2f3+ populations in mouse models. The transcription factor Pou2f3 is a master regulator of the tuft cell lineage. We show that tuft cells are upregulated early during prostate cancer development, and their numbers increase with progression. Cancer-associated tuft cells in the mouse prostate express DCLK1, COX1, COX2, while human tuft cells express COX1. Mouse and human tuft cells exhibit strong activation of signaling pathways including EGFR and SRC-family kinases. While DCLK1 is a mouse tuft cell marker, it is not present in human prostate tuft cells. Tuft cells that appear in mouse models of prostate cancer display genotype-specific tuft cell gene expression signatures. Using bioinformatic analysis tools and publicly available datasets, we characterized prostate tuft cells in aggressive disease and highlighted differences between tuft cell populations. Our findings indicate that tuft cells contribute to the prostate cancer microenvironment and may promote development of more advanced disease. Further research is needed to understand contributions of tuft cells to prostate cancer progression.
Metabolism-related brain morphology accelerates aging and predicts neurodegenerative diseases and stroke: a UK Biobank study
Authors: Shen Chenye , Liu Chaoqiang , Qiu Anqi
Published: June 2023

Abstracts

Metabolic syndrome (MetS) is characterized by a constellation of metabolic risk factors, including obesity, hypertriglyceridemia, low high-density lipoprotein (HDL) levels, hypertension, and hyperglycemia, and is associated with stroke and neurodegenerative diseases. This study capitalized on brain structural images and clinical data from the UK Biobank and explored the associations of brain morphology with MetS and brain aging due to MetS. Cortical surface area, thickness, and subcortical volumes were assessed using FreeSurfer. Linear regression was used to examine associations of brain morphology with five MetS components and the MetS severity in a metabolic aging group (N = 23,676, age 62.8 ± 7.5 years). Partial least squares (PLS) were employed to predict brain age using MetS-associated brain morphology. The five MetS components and MetS severity were associated with increased cortical surface area and decreased thickness, particularly in the frontal, temporal, and sensorimotor cortex, and reduced volumes in the basal ganglia. Obesity best explained the variation of brain morphology. Moreover, participants with the most severe MetS had brain age 1-year older than those without MetS. Brain age in patients with stroke (N = 1042), dementia (N = 83), Parkinson’s (N = 107), and multiple sclerosis (N = 235) was greater than that in the metabolic aging group. The obesity-related brain morphology had the leading discriminative power. Therefore, the MetS-related brain morphological model can be used for risk assessment of stroke and neurodegenerative diseases. Our findings suggested that prioritizing adjusting obesity among the five metabolic components may be more helpful for improving brain health in aging populations.
Psychological resilience mediates the protective role of default-mode network functional connectivity against COVID-19 vicarious traumatization
Authors: Liu Xiqin , Zhao Yajun , Suo Xueling , Zhang Xun , Pan Nanfang , Kemp Graham J. , Gong Qiyong , Wang Song
Published: June 2023

Vicarious traumatization (VT), a negative reaction to witnessing others’ trauma, has been experienced by some people during the COVID-19 pandemic, and can lead to mental health problems. This study aimed to identify functional brain markers of COVID-specific VT and explore the psychological mechanism underlying the brain-VT link. One hundred healthy participants underwent resting-state functional magnetic resonance imaging before the pandemic (October 2019–January 2020) and completed VT measurement during the pandemic (February–April 2020). Whole-brain correlation analysis based on global functional connectivity density (FCD) mapping revealed that VT was negatively correlated with FCD in the right inferior temporal gyrus (ITG) (i.e., the lower FCD in ITG, the worse the VT), identified by mapping onto known large-scale networks as part of the default-mode network (DMN). Resting-state functional connectivity (RSFC) analysis using ITG as seed found that VT was predicted by lower functional connectivity between ITG and other DMN regions including left medial prefrontal cortex, left orbitofrontal cortex, right superior frontal gyrus, right inferior parietal lobule and bilateral precuneus (i.e., the lower the ITG-DMN connectivity, the worse the VT). Mediation analyses suggested that psychological resilience served as a mediator in these associations of ITG FCD and ITG-DMN RSFC with VT. Our results provide novel evidence on the brain basis of VT and emphasize psychological resilience as an important link from DMN functional connectivity to COVID-specific-VT. This may facilitate public health interventions by helping identify individuals at risk of stress- and trauma-related psychopathologies.
Efficacy evaluation of chimeric antigen receptor-modified human peritoneal macrophages in the treatment of gastric cancer
Authors: Dong Xuhui , Fan Jiqiang , Xie Wangxu , Wu Xiang , Wei Jia , He Zhonglei , Wang Wenxin , Wang Xueting , Shen Pingping , Bei Yuncheng
Published: June 2023

Background

Gastric cancer is one of the most common cancers. Peritoneal carcinomatosis (PC) appears to be the most common pattern of recurrence, and more than half of the GC patients eventually die from PC. Novel strategies for the management of patients with PC are urgently needed. Recently, rapid progress has been made in adoptive transfer therapy by using macrophages as the effector cells due to their capabilities of phagocytosis, antigen presentation, and high penetration. Here, we generated a novel macrophage-based therapy and investigated anti-tumoral effects on GC and potential toxicity.

Methods

We developed a novel Chimeric Antigen Receptor-Macrophage (CAR-M) based on genetically modifying human peritoneal macrophages (PMs), expressing a HER2-FcεR1γ-CAR (HF-CAR). We tested HF-CAR macrophages in a variety of GC models in vitro and in vivo.

Results

HF-CAR-PMs specifically targeted HER2-expressed GC, and harboured the FcεR1γ moieties to trigger engulfment. Intraperitoneal administration of HF-CAR-PMs significantly facilitated the HER2-positive tumour regression in PC mouse model and prolonged the overall survival rate. In addition, the combined use of oxaliplatin and HF-CAR-PMs exhibited significantly augment anti-tumour activity and survival benefit.

Conclusions

HF-CAR-PMs could represent an exciting therapeutic option for patients with HER2-positive GC cancer, which should be tested in carefully designed clinical trials.
Blocking tri-methylguanosine synthase 1 (TGS1) stops anchorage-independent growth of canine sarcomas
Authors: Zucko Dora , Boris-Lawrie Kathleen
Published: June 2023

Tri methylguanosine synthase 1 (TGS1) is the enzyme that hyper methylates the hallmark 7-methyl-guanosine cap (m7G-cap) appended to the transcription start site of RNAs. The m7G-cap and the eIF4E-cap binding protein guide canonical cap-dependent translation of mRNAs, whereas hyper methylated cap, m2,2,7G-cap (TMG) lacks adequate eIF4E affinity and licenses entry into a different translation initiation pathway. The potential role for TGS1 and TMG-capped mRNA in neoplastic growth is unknown. Canine sarcoma has high translational value to the human disease. Cumulative downregulation of protein synthesis in osteosarcoma OSCA-40 was achieved cooperatively by siTGS1 and Torin-1. Torin-1 inhibited the proliferation of three canine sarcoma explants in a reversible manner that was eliminated by siRNA-downregulation of TGS1. TGS1 failure prevented the anchorage-independent growth of osteo- and hemangio-sarcomas and curtailed sarcoma recovery from mTOR inhibition. RNA immunoprecipitation studies identified TMG-capped mRNAs encoding TGS1, DHX9 and JUND. TMG-tgs1 transcripts were downregulated by leptomycin B and TGS1 failure was compensated by eIF4E mRNP-dependent tgs1 mRNA translation affected by mTOR. The evidence documents TMG-capped mRNAs are hallmarks of the investigated neoplasms and synergy between TGS1 specialized translation and canonical translation is involved in sarcoma recovery from mTOR inhibition. Therapeutic targeting of TGS1 activity in cancer is ripe for future exploration.
Biallelic FBXW7 knockout induces AKAP8-mediated DNA damage in neighbouring wildtype cells
Authors: Chan Dedrick Kok Hong , Mandal Amit , Hester Svenja , Yu Zhanru , Higgins Geoff Stuart , Kessler Benedikt Mathias , Fischer Roman , Buczacki Simon James Alexander
Published: June 2023

Colorectal cancer possesses marked intratumoral heterogeneity. While subclonal interactions between Vogelstein driver mutations have been extensively studied, less is known about competitive or cooperative effects between subclonal populations with other cancer driver mutations. FBXW7 is a cancer driver mutation which is present in close to 17% of colorectal cancer cells. In this study, we generated isogenic FBXW7 mutant cells using CRISPR-Cas9. We identified an upregulation of oxidative phosphorylation and DNA damage in FBXW7 mutant cells, which surprisingly proliferated at a decreased rate compared to wildtype cells. To determine subclonal interactions, wildtype and mutant FBXW7 cells were cocultured using a Transwell system. Wildtype cells cocultured with FBXW7 mutant cells similarly developed DNA damage which was not observed when wildtype cells were co-cultured with other wildtype cells, suggesting that FBXW7 mutant cells were inducing DNA damage in neighbouring wildtype cells. Using mass spectrometry, we identified AKAP8 as being secreted by FBXW7 mutant cells into the coculture media. Furthermore, overexpression of AKAP8 in wildtype cells recapitulated the DNA damage phenotype observed during coculture, while co-culture of wildtype cells with double mutant FBXW7−/−/AKAP8−/− cells abrogated the DNA damage phenotype. Here, we describe a hitherto unknown phenomenon of AKAP8-mediated DNA damage from FBXW7 mutant to neighbouring wildtype cells. Our findings demonstrate the importance of elucidating the local effect of cancer driver mutations between subclonal populations.
MicroRNA-375 restrains the progression of lung squamous cell carcinoma by modulating the ERK pathway via UBE3A-mediated DUSP1 degradation
Authors: Gan Junqing , Zhang Yu , Liu Shan , Mu Guannan , Zhao Juan , Jiang Wei , Li Jiade , Li Qi , Wu Yangjiazi , Wang Xinling , Che Dehai , Li Xiaomei , Huang Xiaoyi , Meng Qingwei
Published: June 2023

MiRNA-375 has been reported to play critical roles in a variety of cancers. To unravel its biological roles, especially its specific mechanisms of action in lung squamous cell carcinoma (LUSC), LUSC tissue microarrays and miRNAscope were performed to identify the miR-375 expression. Associations with clinicopathologic features, survival, and the prognostic value of miR-375 in LUSC were clarified in a retrospective study of 90 pairs of LUSC tissues. In vitro and in vivo gain- and loss-of-function assays were conducted to validate the effects and mechanism of miR-375 in LUSC. The mechanism responsible for interactions was verified by dual-luciferase reporter gene assay, immunoprecipitation (IP) analysis, immunofluorescence (IF) assay and ubiquitination assay. We found that miR-375 had higher expression in noncancerous adjacent tissues than in LUSC tissues. Clinicopathologic analyses showed that miR-375 expression was correlated with pathologic stage and was an independent predictor of overall survival (OS) for LUSC. MiR-375, as a tumor inhibitor, inhibited proliferation and metastasis while promoting apoptosis of LUSC cells. Mechanistic research indicated that miR-375 targeted ubiquitin-protein ligase E3A (UBE3A), which in turn promoted the activity of the ERK signaling pathway via ubiquitin-mediated dual-specificity protein phosphatase 1 (DUSP1) degradation. Collectively, we propose a novel mechanism of tumorigenesis and metastasis of LUSC via the miR-375/UBE3A/DUSP1/ERK axis, which could potentially facilitate new strategies for the treatment of LUSC.
Long-term effects of SARS-CoV-2 infection on human brain and memory
Authors: Ding Qiulu , Zhao HanJun
Published: June 2023

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have caused several waves of outbreaks. From the ancestral strain to Omicron variant, SARS-CoV-2 has evolved with the high transmissibility and increased immune escape against vaccines. Because of the multiple basic amino acids in the S1-S2 junction of spike protein, the widespread distribution of angiotensin-converting enzyme 2 (ACE2) receptor in human body and the high transmissibility, SARS-CoV-2 can infect multiple organs and has led to over 0.7 billion infectious cases. Studies showed that SARS-CoV-2 infection can cause more than 10% patients with the Long-COVID syndrome, including pathological changes in brains. This review mainly provides the molecular foundations for understanding the mechanism of SARS-CoV-2 invading human brain and the molecular basis of SARS-CoV-2 infection interfering with human brain and memory, which are associated with the immune dysfunction, syncytia-induced cell death, the persistence of SARS-CoV-2 infection, microclots and biopsychosocial aspects. We also discuss the strategies for reducing the Long-COVID syndrome. Further studies and analysis of shared researches will allow for further clarity regarding the long-term health consequences.
Single-cell transcriptomics uncovers EGFR signaling-mediated gastric progenitor cell differentiation in stomach homeostasis
Authors: Takada Hitomi , Sasagawa Yohei , Yoshimura Mika , Tanaka Kaori , Iwayama Yoshimi , Hayashi Tetsutaro , Isomura-Matoba Ayako , Nikaido Itoshi , Kurisaki Akira
Published: June 2023

Defects in gastric progenitor cell differentiation are associated with various gastric disorders, including atrophic gastritis, intestinal metaplasia, and gastric cancer. However, the mechanisms underlying the multilineage differentiation of gastric progenitor cells during healthy homeostasis remain poorly understood. Here, using a single-cell RNA sequencing method, Quartz-Seq2, we analyzed the gene expression dynamics of progenitor cell differentiation toward pit cell, neck cell, and parietal cell lineages in healthy adult mouse corpus tissues. Enrichment analysis of pseudotime-dependent genes and a gastric organoid assay revealed that EGFR-ERK signaling promotes pit cell differentiation, whereas NF-κB signaling maintains gastric progenitor cells in an undifferentiated state. In addition, pharmacological inhibition of EGFR in vivo resulted in a decreased number of pit cells. Although activation of EGFR signaling in gastric progenitor cells has been suggested as one of the major inducers of gastric cancers, our findings unexpectedly identified that EGFR signaling exerts a differentiation-promoting function, not a mitogenic function, in normal gastric homeostasis.