bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene polymorphisms of molecules of the cGAS-STING signalling pathway are associated with AML in Chinese patients
Authors: Ma Yuechan , Wang Dongmei , Feng Lei , Chang Mengyuan , Li Mingying , Meng Guangqiang , Wu Yuyan , Lu Fei , Sun Tao , Ji Chunyan , Ye Jingjing
Published: March 2024

Purpose

The aim of this study was to explore the relationships between single-nucleotide polymorphisms (SNPs) of crucial molecules in the cGAS-STING signalling pathway and the susceptibility to, induction chemotherapy response of, and prognosis of acute myeloid leukaemia (AML) in Chinese patients.

Methods

Thirteen SNPs of crucial molecules in the cGAS-STING signalling pathway were genotyped in 262 AML patients using the Sequenom MassARRAY system. The associations of SNPs with susceptibility, and induction chemotherapy response were analysed using the chi-square test or Fisher’s exact test and univariate binary logistic regression, the connection of SNPs with prognosis of AML was analysed using the log-rank test, and Kaplan–Meier curves were applied for survival estimation.

Results

In our study, gene polymorphisms of cGAS-STING signalling pathway molecules could be vitally associated with AML. In the recessive model, the cGAS rs311678 gene polymorphism could be closely related to AML susceptibility (CC vs. TT + TC, odds ratio (OR) = 0.480, 95% confidence interval (CI) = 0.260–0.889, p = 0.020). Moreover, IKKA rs3808917 might be associated with the WBC count, cGAS rs311678 could be associated with the bone marrow (BM) blast percentage, and NF-κB rs1056890 under codominant and recessive models could be connected with the HGB level. Patients who were STING rs7380272 TT/CT carriers was likely to have higher insensitivity to induction chemotherapy than CC carriers (TT + CT vs. CC, OR = 2.917, 95% CI = 1.073–7.929, p = 0.036). Survival analysis indicated that the IKKB rs3747811 TT genotype might be associated with decreased overall survival (OS) (p < 0.05).

Conclusions

SNPs of molecules in the cGAS-STING signalling pathway could be significantly associated with AML. The cGAS rs311678 gene polymorphism could be associated with AML susceptibility, the STING rs7380272 variant might be related to induction chemotherapy response, and IKKB rs3747811 tended to be associated with AML overall survival. Moreover, IKKA rs3808917 could be associated with the WBC count, cGAS rs311678 could be associated with the BM blast percentage, and NF-κB rs1056890 might be related to the HGB level.
Performance analysis of a novel ejector-assisted condenser outlet split dual-evaporator refrigeration system
Authors: Sachdeva Gulshan , Anuradha Parinam , Jain Vaibhav , VenkataTeja Y. T.
Published: March 2024

The performance of an ejector-assisted condenser outlet split dual-evaporator cycle is compared with a conventional dual-evaporator cycle albeit consisting a pressure reducing valve. The cycles do not employ any separator due to its inability to efficiently separate the liquid and the vapor phases. The comparison of both the cycles has been made for the same cooling capacity in low-temperature evaporator and unit flow rate of R134a and R1234yf as refrigerants. The impacts of changing the operating temperatures of evaporator and condenser have been examined in the current investigation. The study reveals that with the increase in temperature of the high-temperature evaporator, the cooling capacity of the high-temperature evaporator yields, while that of the low-temperature evaporator plummets in both the cycles. Further, the compressor work is allayed in the ejector-assisted cycle; thus, the COP is enhanced considerably. The percentage COP improvement over the basic cycle is obtained from 14.7 to 17.53% for the refrigerant R1234yf and from 14.45 to 17.32% for R134a; however, the COP of both the cycles with R12134yf is slightly lower than with R134a. The ejector has been modeled assuming a constant pressure theory. The observed trend indicates that the entrainment ratio is improved with the rise in the temperature of low-temperature evaporator, whereas it is decreased with the rise in the temperature of high-temperature evaporator.
Initial psychometric evaluation and cross-cultural generalization of the Resilience Evaluation Scale (RES) in college students
Authors: Dai Yan , Petri Jessica M. , Salisbury-Glennon Jill D. , Luan Lingfei , Wang Yuchen , Weathers Frank W.
Published: March 2024

The Resilience Evaluation Scale (RES) is a newly developed measure of resilience written in both English and Dutch languages. To date, there have not been comprehensive psychometric evaluations of the RES’ performance, including validity for use in non-Western cultural populations and languages. In our attempt to address this void, we conducted a psychometric evaluation of the RES utilizing a Western, sample of U.S. college students and non-Western sample of Chinese college students. Our psychometric evaluation of the RES in a Western, English-speaking sample of U.S. college students indicated mixed results on the construct validity of the RES for measuring resilience. We also found that the factor structure of the RES lacked configural invariance across U.S. college student and Chinese college student samples. Results suggested that additional research is needed to assess whether the RES appropriately measures internal factors of resilience or requires modification. We also highlight the need for continued development of cross-culturally valid measures, and possibly different conceptualizations, of resilience across cultural and linguistic groups.
Significance of Raffinose Family Oligosaccharides (RFOs) metabolism in plants
Authors: Liu Huan , Wang Fan , Liu Baohui , Kong Fanjiang , Fang Chao
Published: March 2024

Raffinose Family Oligosaccharides (RFOs) are a kind of polysaccharide containing D-galactose, and they widely exist in higher plants. Synthesis of RFOs begins with galactinol synthase (GolS; EC 2.4.1.123) to convert myo-inositol into galactinol. The subsequent formation of raffinose and stachyose are catalyzed by raffinose synthase (RS; EC 2.4.1.82) and stachyose synthase (STS; EC 2.4.1.67) using sucrose and galactinol as substrate, respectively. The hydrolysis of RFOs is finished by α-galactosidase (α-Gal; EC 3.2.1.22) to produce sucrose and galactose. Importance of RFOs metabolism have been summarized, e.g. In RFOs translocating plants, the phloem loading and unloading of RFOs are widely reported in mediating the plant development process. Interference function of RFOs synthesis or hydrolysis enzymes caused growth defect. In addition, the metabolism of RFOs involved in the biotic or abiotic stresses was discussed in this review. Overall, this literature summarizes our current understanding of RFOs metabolism and points out knowledge gaps that need to be filled in future.
Computational Principles of Mobile Robotics
Authors: Dudek Gregory , Jenkin Michael
Published: March 2024

Now in its third edition, this textbook is a comprehensive introduction to the multidisciplinary field of mobile robotics, which lies at the intersection of artificial intelligence, computational vision, and traditional robotics. Written for advanced undergraduates and graduate students in computer science and engineering, the book covers algorithms for a range of strategies for locomotion, sensing, and reasoning. The new edition includes recent advances in robotics and intelligent machines, including coverage of human-robot interaction, robot ethics, and the application of advanced AI techniques to end-to-end robot control and specific computational tasks. This book also provides support for a number of algorithms using ROS 2, and includes a review of critical mathematical material and an extensive list of sample problems. Researchers as well as students in the field of mobile robotics will appreciate this comprehensive treatment of state-of-the-art methods and key technologies.
Why Didn’t Brazilian Democracy Die?
Authors: Melo Marcus André , Pereira Carlos
Published: March 2024

Brazil, for many scholars and pundits, showcased the risk of democratic breakdown with the election of a far-right populist like Jair Bolsonaro. Against pessimistic expectations, however, not only has Brazilian democracy survived but politics has returned to business as usual. What can explain this supposedly unanticipated outcome? This article provides an analytical assessment of this this puzzle and offers an alternative explanation. We argue that both the diagnoses of Brazilian institutions and the predictions made were misguided. We explore the role played by the Supreme Court, party system, media, and congressional politics in restricting Bolsonaro’s illiberal initiatives.
#Resistencia: Indigenous Movements, Social Media, and Mobilization in Latin America
Authors: Lupien Pascal , Rincón Adriana , Lalama Vargas Andrés , Machaca Soledad , Chiriboga Gabriel
Published: March 2024

Indigenous peoples in Latin America have produced some of the region’s strongest and most enduring social movements, drawing on a diverse repertoire of contention to pursue their goals. In the twenty-first century, social media have transformed the landscape of collective action, compelling Indigenous movements to navigate the evolving dynamics of digital platforms. There is an ongoing debate in the literature regarding the role of social media in mobilization. But we know relatively little about how social media fit into the tactical repertoires of Indigenous actors and what tasks these platforms are used for. This article addresses this gap through an examination of how Indigenous actors use social media during protest events. We conducted a comparative analysis of social media content produced by Indigenous social movement organizations during major protest events in three countries from 2018 to 2019. We find that the most common functions include activating supporters and exposing state violence. These functions support several of the organizations’ core mobilization tasks by providing actors with tools to complement collection action.
An Insurgent Mood: Lorraine Hansberry on the Politics of Home
Authors: ADALET BEGÜM
Published: March 2024

This article takes as its starting point a 1961 conversation between James Baldwin and Lorraine Hansberry, where the latter first posed the question that would recur in Baldwin’s writings in the following years: “Is it necessary to integrate oneself into a burning house?” Although the phrase is often associated with Baldwin, who mostly used it as a metaphor for the racist nation, most famously in The Fire Next Time (1963), this article shows how Hansberry’s analysis of many African Americans’ skepticism toward integration into a “burning house” was situated in a global context of anticolonial, anti-capitalist, and feminist struggle. Writing within networks of Black internationalist feminists and presenting a multivalent and relational account of home, Hansberry revealed household labor and relations of intimacy to be central to the making and maintenance of empire, racism, and capitalism, as well as their contestation through acts and affects of insurgency.
The effects of replacing ghee with rapeseed oil on liver steatosis and enzymes, lipid profile, insulin resistance and anthropometric measurements in patients with non-alcoholic fatty liver disease: a randomised controlled clinical trial
Authors: Maleki Sedgi Fatemeh , Mohammad Hosseiniazar Mohammadreza , Alizadeh Mohammad
Published: March 2024

Non-alcoholic fatty liver disease (NAFLD), which is a prevalent hepatic condition worldwide, is expected to develop into the leading reason for end-stage fatty liver in the forthcoming decades. Incorporating rapeseed oil into a balanced diet may be beneficial in improving NAFLD. The goal of this trial was to evaluate the impact of substituting ghee with rapeseed oil on primary outcomes such as fatty liver and liver enzymes, as well as on secondary outcomes including glycaemic variables, lipid profile and anthropometric measurements in individuals with NAFLD. Over 12 weeks, 110 patients (seventy men and forty women; BMI (mean) 28·2 (sd 1·6 kg/m2); mean age 42 (sd 9·6) years), who daily consumed ghee, were assigned to the intervention or control group through random allocation. The intervention group was advised to substitute ghee with rapeseed oil in the same amount. The control group continued the consumption of ghee and was instructed to adhere to a healthy diet. Results showed a significant reduction in the steatosis in the intervention group in comparison with the control group (P < 0·001). However, a significant change in the levels of alanine aminotransferase (–14·4 μg/l), γ-glutamyl transferase (–1·8 μg/l), TAG (–39·7 mg/dl), total cholesterol (–17·2 mg/dl), LDL (–7·5 mg/dl), fasting blood glucose (–7·5 mg/dl), insulin (–3·05 mU/l), Homeostatic Model Assessment for Insulin Resistance (–0·9), Quantitative Insulin-Sensitivity Check Index (+0·01), weight (–4·3 kg), BMI (–0·04 kg/m2), waist (–5·6 cm) and waist:height ratio (–0·04) was seen in the intervention group. The consumption of rapeseed oil instead of ghee caused improvements in liver steatosis and enzymes, glycaemic variables and anthropometric measurements among individuals with NAFLD.
Perspectives
Authors: Tentler Leslie Woodcock
Published: March 2024

John McGreevy has written a book of such breadth and erudition as to daunt a would-be reviewer. How to evaluate so formidable an achievement? One could, of course, devote one's allotted paragraphs exclusively to praise, all of which would be merited. (McGreevy's engaging prose would come in for prominent mention.) But what then of the critical eye that every reviewer hopes to train on even the most accomplished work of scholarship? McGreevy himself suggests a way out: “Specialists will regret what is missing,” he notes in the book's introduction, “and rightly so.” Given the remarkable range of subjects the book actually covers, however, quibbling over its inevitable omissions seems neither charitable nor fruitful. Best, perhaps, to “think out loud” about the impact of McGreevy's global perspective on my own assumptions as a historian of American Catholicism. Needless to say, his is a book from which I learned a great deal.
Introduction for John T. McGreevy, Catholicism: A Global History from the French Revolution to Pope Francis (2022)
Authors: Robert Dana L.
Published: March 2024

Approximately one third of the world is Christian, and half of those are Roman Catholics. The demographics alone make writing a global history of Catholicism a mammoth task. To attempt the impossible, Professor John T. McGreevy of Notre Dame University has tackled a theme that plays itself out over multiple centuries and diverse cultural settings—the conversation, negotiation, tension, and conflict between traditionalism and modernization. Given that conservatism and progressivism shift meanings according to historical context, the implications of each position in situ are complex and surprising. Only a scholar of McGreevy's maturity and erudition could hope to succeed in such a bold enterprise.
Africa in the Global Church?
Authors: Enyegue Jean Luc
Published: March 2024

John McGreevy's Catholicism: A Global History from the French Revolution to Pope Francis hinges on seismic events that shook the foundations of the Catholic Church: the French Revolution, its aftershocks in many European nations, and the devastating effects of the Napoleonic Wars that followed. The episcopalism of Catholicism that arose from the ashes of the revolution seemed to reject the pillar of its globalism, namely the papacy. Pius IX paid for this with his life. Eternal Rome suddenly became mortal, overtaken by the revolutionaries. Catholic schools were nationalized. The Civil Constitution of the Clergy enacted an agenda for the secularization of society, the church itself, and its institutions. Notre Dame became a “Temple of Reason,” and the chalices and ciboria of Saint-Sulpice were melted down to make cash. The damage done to the church by this revolution was paralleled only by the communist revolutions of the twentieth century.
Unexplained Revolutions: The Origins and Ends of Latin American Catholic Upheaval
Authors: Scheper Hughes Jennifer
Published: March 2024

John T. McGreevy's chronicle of modern Roman Catholic history is a vivid and sometimes jarring reminder of the historical depth of contemporary divisions within the Church, especially as these enter the public sphere. Catholicism: A Global History from the French Revolution to Pope Francis elucidates the church's ambivalent response to the challenge of modernity over the long nineteenth and twentieth centuries, specifically the rise of democratic nation states, anti-colonialist movements from the global south, the struggles of poor and working people for liberation, and feminist and human rights movements. The spread of totalitarianism and the supposed triumph of capitalism represented a different set of challenges for the church in this period.
Discounted densities of overshoot and undershoot for Lévy processes with applications in finance
Authors: Gao Hui , Yin Chuancun
Published: March 2024

This paper considers the first passage times to constant boundaries and the two-sided exit problem for Lévy process with a characteristic exponent in which at least one of the two jumps having rational Laplace transforms. The joint distribution of the first passage times and undershoot/overshoot are obtained. The processes recover many models that have appeared in the literature such as the compound Poisson risk models, the perturbed compound Poisson risk models, and their dual ones. As applications, we obtain the solutions for popular path-dependent options such as lookback and barrier options in terms of Laplace transforms.
Analysis of emission line spectra of active galaxies and fine classification for activity types
Authors: Mickaelian A. M. , Abrahamyan H. V. , Paronyan G. M. , Mikayelyan G. A.
Published: March 2024

Using the SDSS spectroscopy, we have carried out fine optical spectral classification for activity types for 710 AGN candidates. These objects come from a larger sample of some 2,500 candidate AGN using pre-selection by various samples; bright objects of the Catalog of Quasars and Active Galactic Nuclei, AGN candidates among X-ray sources, optically variable radio sources, IRAS extragalactic objects, etc. A number of papers have been published with the results of this spectral classification. More than 800 QSOs have been identified and classified, including 710 QSOs, Seyferts and Composites. The fine classification shows that many QSOs show the same features as Seyferts, i.e., subtypes between S1 and S2 (S1.2, S1.5, S1.8 and S1.9). We have introduced subtypes for the QSOs: QSO1.2, QSO1.5, QSO1.8, QSO1.9, though the last subtype does not appear in SDSS wavelength range due to mostly highly redshifted Hα (the main line for identification of the 1.9 subtype). Thus, independent of the luminosity (which serves as a separator between QSOs and Seyferts), AGN show the same features. We also have classified many objects as Composites, spectra having composite characteristics between Sy and LINERs, Sy and HII or LINERs and HII; in some cases all three characteristics appear together resulting as Sy/LINER/HII subtype. The QSOs subtypes together with Seyfert ones allow to follow AGN properties along larger redshift range expanding our knowledge on the evolution of AGN to more distant Universe represented by QSOs.
Legacy of Charlotte Moore Sitterly in the Internet Age
Authors: Kramida Alexander
Published: March 2024

Most (yet not all) results of atomic physics research of Charlotte Moore Sitterly (CMS), which was closely connected to astrophysics, are now incorporated in online databases, one of which is the Atomic Spectra Database of the National Institute of Standards and Technology. The use of this database extends far beyond astrophysics, but this review focuses on astrophysical applications. The impact of CMS’s work on modern atomic physics and other sciences is discussed, and problems that urgently need solutions are outlined.
Atomic and Molecular Databases Open Science for a sustainable world
Authors: Dubernet M. L. , Berriman G.B. , Barklem P. , Choi K. , Foster A. , Gordon I. , Hill C. , Kim J. , Kwon D.H. , Linnartz H. , Ralchenko Yu. , Salama F. , Shmagun H. , Schilke P. , Seo D. , Shim J. , Shin S. , Song M.-Y. , Tennyson J. , Vastel C.
Published: March 2024

The building of online atomic and molecular databases for astrophysics and for other research fields started with the beginning of the internet. These databases have encompassed different forms: databases of individual research groups exposing their own data, databases providing collected data from the refereed literature, databases providing evaluated compilations, databases providing repositories for individuals to deposit their data, and so on. They were, and are, the replacement for literature compilations with the goal of providing more complete and in particular easily accessible data services to the users communities. Such initiatives involve not only scientific work on the data, but also the characterization of data, which comes with the “standardization” of metadata and of the relations between metadata, as recently developed in different communities. This contribution aims at providing a representative overview of the atomic and molecular databases ecosystem, which is available to the astrophysical community and addresses different issues linked to the use and management of data and databases. The information provided in this paper is related to the keynote lecture “Atomic and Molecular Databases: Open Science for better science and a sustainable world” whose slides can be found at DOI : doi.org/10.5281/zenodo.6979352 on the Zenodo repository connected to the “cb5-labastro” Zenodo Community (https://zenodo.org/communities/cb5-labastro).
The Importance of Producing and Characterizing Laboratory Analogs of (Exo)Planetary Atmospheric Aerosols
Authors: Sciamma-O’Brien Ella , Hörst Sarah M. , Roush Ted L. , Salama Farid
Published: March 2024

Experimental studies are key to investigating the physical and chemical processes that drive cloud and haze formation from gas and solid phase molecular precursors in (exo)planetary environments, and validating the theoretical calculations used in models of (exo)planetary atmospheres. They allow characterizing the physical, optical, and chemical properties of laboratory-generated analogs, hence providing critical input parameters to models for observational data analysis. In this paper, we present examples of (1) experiments performed with different facilities to produce analogs of Titan and exoplanet atmospheric aerosols from gas phase molecular precursors, and (2) the characterization of these analogs to provide information on their composition, morphology, and optical constants to the scientific community. We also introduce the recently launched NASA Center for Optical Constants (NCOC), which will provide this critical data to the scientific community for (exo)planetary-relevant ices and organic refractory materials produced in the laboratory from the irradiation of gas and ice precursors.
Land Data Assimilation: Harmonizing Theory and Data in Land Surface Process Studies
Authors: Li Xin , Liu Feng , Ma Chunfeng , Hou Jinliang , Zheng Donghai , Ma Hanqing , Bai Yulong , Han Xujun , Vereecken Harry , Yang Kun , Duan Qingyun , Huang Chunlin
Published: March 2024

Data assimilation plays a dual role in advancing the “scientific” understanding and serving as an “engineering tool” for the Earth system sciences. Land data assimilation (LDA) has evolved into a distinct discipline within geophysics, facilitating the harmonization of theory and data and allowing land models and observations to complement and constrain each other. Over recent decades, substantial progress has been made in the theory, methodology, and application of LDA, necessitating a holistic and in‐depth exploration of its full spectrum. Here, we present a thorough review elucidating the theoretical and methodological developments in LDA and its distinctive features. This encompasses breakthroughs in addressing strong nonlinearities in land surface processes, exploring the potential of machine learning approaches in data assimilation, quantifying uncertainties arising from multiscale spatial correlation, and simultaneously estimating model states and parameters. LDA has proven successful in enhancing the understanding and prediction of various land surface processes (including soil moisture, snow, evapotranspiration, streamflow, groundwater, irrigation and land surface temperature), particularly within the realms of water and energy cycles. This review outlines the development of global, regional, and catchment‐scale LDA systems and software platforms, proposing grand challenges of generating land reanalysis and advancing coupled land‒atmosphere DA. We lastly highlight the opportunities to expand the applications of LDA from pure geophysical systems to coupled natural and human systems by ingesting a deluge of Earth observation and social sensing data. The paper synthesizes current LDA knowledge and provides a steppingstone for its future development, particularly in promoting dual driven theory‐data land processes studies.
The Role of the Peak Radius of Maximum Wind Contraction Rate Preceding the Peak Intensification Rate on Tropical Cyclone Lifetime Maximum Intensity
Authors: Wang Yilei , Wu Qiaoyan
Published: March 2024

The prevalence of the maximum radius of maximum wind (RMW) contraction rate for the tropical cyclone (TC) before the maximum TC intensification rate has been observed in several previous studies. However, it remains unclear whether and how the maximum RMW contraction rate preceding the maximum TC intensification rate affects the TC lifetime maximum intensity (LMI). In this study, tropical cyclones are grouped into three types depending on whether the peak RMW contraction rate precedes, occurs simultaneously with, or lags the time of the peak intensification rate in the North Atlantic and western North Pacific. Results indicate that when the maximum RMW contraction rate occurs before the maximum intensification rate, TCs are more likely to gain a greater LMI. TCs with the time of maximum RMW contraction rate preceding the time of the maximum intensification rate are more likely to achieve a small RMW and intermediate intensity after the maximum RMW contraction rate period, which is conducive to higher intensification rates. An intermediate initial intensity and higher maximum intensification rate both lead to a greater LMI. Environmental factors are also examined but are found to have little impact on the LMI for the three types of TCs. This work suggests that TCs with a higher LMI are often characterized by a notable maximum rate of RMW contraction before the peak intensification rate and helps to a better understanding of TC structure and intensity changes.
Sensitivity of Simulated Fire‐Generated Circulations to Fuel Characteristics During Large Wildfires
Authors: Roberts Matthew , Lareau Neil P. , Juliano Timothy W. , Shamsaei Kasra , Ebrahimian Hamed , Kosovic Branko
Published: March 2024

Coupled fire‐atmosphere models often struggle to simulate important fire processes like fire generated flows, deep flaming fronts, extreme updrafts, and stratospheric smoke injection during large wildfires. This study uses the coupled fire‐atmosphere model, WRF‐Fire, to examine the sensitivities of some of these phenomena to the modeled total fuel load and its consumption. Specifically, the 2020 Bear Fire and 2021 Caldor Fire in California's Sierra Nevada are simulated using three fuel loading scenarios (1X, 4X, and 8X LANDFIRE derived surface fuel), while controlling the fire rate of spread using observations. This approach helps isolate the fuel loading and consumption needed to produce fire‐generated winds and plume rise comparable to radar observations of these events. Increasing fuel loads and corresponding fire residence time in WRF‐Fire leads to deep plumes in excess of 10 km, strong vertical velocities of 40–45 m s−1, and combustion fronts several kilometers in width (in the along wind direction). These results indicate that LANDFIRE‐based surface fuel loads in WRF‐Fire likely under‐represent fuel loading, having significant implications for simulating landscape‐scale wildfire processes, associated impacts on spread, and fire‐atmosphere feedbacks.
Estimating π Using the Topography of the Terrestrial Planets
Authors: Vasseur Jérémie , Wadsworth Fabian B.
Published: March 2024

It is π‐day 2024 (March 14th) and to celebrate, we ask the question: can π be estimated accurately using the shape of the terrestrial planets and the Moon? We proceed by using models for the planet topographies in slices of constant latitude and computing π as the ratio of the circumference to the diameter in each slice. We define the circumference as the topographically undulating perimeter of the slice (which deviates from the circular section of the reference ellipsoid). We define the diameter as the distance connecting two opposite points on the topography model through the center of the slice. This gives us a distribution of π estimates for each latitude slice and overall for each planetary body. The distribution and accuracy of the π estimates we compute are a representation of how smooth and circular latitude slices of the terrestrial planets are. We find that Mercury and Venus are particularly good at predicting π because they are relatively smooth and the topographic deviations from the reference ellipsoid are small compared with Mars, Earth, and the Moon. In the spirit of π‐day, this mathematical exercise motivates an interest in planetary geophysics and shape.
Gephyrin phosphorylation facilitates sexually dimorphic development and function of parvalbumin interneurons in the mouse hippocampus
Authors: Campbell Benjamin F. N. , Cruz-Ochoa Natalia , Otomo Kanako , Lukacsovich David , Espinosa Pedro , Abegg Andrin , Luo Wenshu , Bellone Camilla , Földy Csaba , Tyagarajan Shiva K.
Published: March 2024

The precise function of specialized GABAergic interneuron subtypes is required to provide appropriate synaptic inhibition for regulating principal neuron excitability and synchronization within brain circuits. Of these, parvalbumin-type (PV neuron) dysfunction is a feature of several sex-biased psychiatric and brain disorders, although, the underlying developmental mechanisms are unclear. While the transcriptional action of sex hormones generates sexual dimorphism during brain development, whether kinase signaling contributes to sex differences in PV neuron function remains unexplored. In the hippocampus, we report that gephyrin, the main inhibitory post-synaptic scaffolding protein, is phosphorylated at serine S268 and S270 in a developmentally-dependent manner in both males and females. When examining GphnS268A/S270A mice in which site-specific phosphorylation is constitutively blocked, we found that sex differences in PV neuron density in the hippocampal CA1 present in WT mice were abolished, coincident with a female-specific increase in PV neuron-derived terminals and increased inhibitory input onto principal cells. Electrophysiological analysis of CA1 PV neurons indicated that gephyrin phosphorylation is required for sexually dimorphic function. Moreover, while male and female WT mice showed no difference in hippocampus-dependent memory tasks, GphnS268A/S270A mice exhibited sex- and task-specific deficits, indicating that gephyrin phosphorylation is differentially required by males and females for convergent cognitive function. In fate mapping experiments, we uncovered that gephyrin phosphorylation at S268 and S270 establishes sex differences in putative PV neuron density during early postnatal development. Furthermore, patch-sequencing of putative PV neurons at postnatal day 4 revealed that gephyrin phosphorylation contributes to sex differences in the transcriptomic profile of developing interneurons. Therefore, these early shifts in male-female interneuron development may drive adult sex differences in PV neuron function and connectivity. Our results identify gephyrin phosphorylation as a new substrate organizing PV neuron development at the anatomical, functional, and transcriptional levels in a sex-dependent manner, thus implicating kinase signaling disruption as a new mechanism contributing to the sex-dependent etiology of brain disorders.
The role of RNA-modifying proteins in renal cell carcinoma
Authors: Alhammadi Muna A. , Bajbouj Khuloud , Talaat Iman M. , Hamoudi Rifat
Published: March 2024

Gene expression is one of the most critical cellular processes. It is controlled by complex mechanisms at the genomic, epigenomic, transcriptomic, and proteomic levels. Any aberration in these mechanisms can lead to dysregulated gene expression. One recently discovered process that controls gene expression includes chemical modifications of RNA molecules by RNA-modifying proteins, a field known as epitranscriptomics. Epitranscriptomics can regulate mRNA splicing, nuclear export, stabilization, translation, or induce degradation of target RNA molecules. Dysregulation in RNA-modifying proteins has been found to contribute to many pathological conditions, such as cancer, diabetes, obesity, cardiovascular diseases, and neurological diseases, among others. This article reviews the role of epitranscriptomics in the pathogenesis and progression of renal cell carcinoma. It summarizes the molecular function of RNA-modifying proteins in the pathogenesis of renal cell carcinoma.
COVID-19 related neurological manifestations in Parkinson’s disease: has ferroptosis been a suspect?
Authors: Jia Fengju , Han Jing
Published: March 2024

A rising number of patient cases point to a probable link between SARS-CoV-2 infection and Parkinson’s disease (PD), yet the mechanisms by which SARS-CoV-2 affects the brain and generates neuropsychiatric symptoms in COVID-19 patients remain unknown. Ferroptosis, a distinct iron-dependent non-apoptotic type of cell death characterized by lipid peroxidation and glutathione depletion, a key factor in neurological disorders. Ferroptosis may have a pathogenic role in COVID-19, according to recent findings, however its potential contributions to COVID-19-related PD have not yet been investigated. This review covers potential paths for SARS-CoV-2 infection of the brain. Among these putative processes, ferroptosis may contribute to the etiology of COVID-19-associated PD, potentially providing therapeutic methods.
RBBP6 maintains glioblastoma stem cells through CPSF3-dependent alternative polyadenylation
Authors: Lin Peng , Chen Wenyan , Long Zhilin , Yu Jichuan , Yang Jiayao , Xia Zhen , Wu Qiulian , Min Xinyu , Tang Jing , Cui Ya , Liu Fuyi , Wang Chun , Zheng Jian , Li Wei , Rich Jeremy N. , Li Lei , Xie Qi
Published: March 2024

Glioblastoma is one of the most lethal malignant cancers, displaying striking intratumor heterogeneity, with glioblastoma stem cells (GSCs) contributing to tumorigenesis and therapeutic resistance. Pharmacologic modulators of ubiquitin ligases and deubiquitinases are under development for cancer and other diseases. Here, we performed parallel in vitro and in vivo CRISPR/Cas9 knockout screens targeting human ubiquitin E3 ligases and deubiquitinases, revealing the E3 ligase RBBP6 as an essential factor for GSC maintenance. Targeting RBBP6 inhibited GSC proliferation and tumor initiation. Mechanistically, RBBP6 mediated K63-linked ubiquitination of Cleavage and Polyadenylation Specific Factor 3 (CPSF3), which stabilized CPSF3 to regulate alternative polyadenylation events. RBBP6 depletion induced shortening of the 3’UTRs of MYC competing-endogenous RNAs to release miR-590-3p from shortened UTRs, thereby decreasing MYC expression. Targeting CPSF3 with a small molecular inhibitor (JTE-607) reduces GSC viability and inhibits in vivo tumor growth. Collectively, RBBP6 maintains high MYC expression in GSCs through regulation of CPSF3-dependent alternative polyadenylation, providing a potential therapeutic paradigm for glioblastoma.
In-section Click-iT detection and super-resolution CLEM analysis of nucleolar ultrastructure and replication in plants
Authors: Franek Michal , Koptašíková Lenka , Mikšátko Jíří , Liebl David , Macíčková Eliška , Pospíšil Jakub , Esner Milan , Dvořáčková Martina , Fajkus Jíří
Published: March 2024

Correlative light and electron microscopy (CLEM) is an important tool for the localisation of target molecule(s) and their spatial correlation with the ultrastructural map of subcellular features at the nanometre scale. Adoption of these advanced imaging methods has been limited in plant biology, due to challenges with plant tissue permeability, fluorescence labelling efficiency, indexing of features of interest throughout the complex 3D volume and their re-localization on micrographs of ultrathin cross-sections. Here, we demonstrate an imaging approach based on tissue processing and embedding into methacrylate resin followed by imaging of sections by both, single-molecule localization microscopy and transmission electron microscopy using consecutive CLEM and same-section CLEM correlative workflow. Importantly, we demonstrate that the use of a particular type of embedding resin is not only compatible with single-molecule localization microscopy but shows improvements in the fluorophore blinking behavior relative to the whole-mount approaches. Here, we use a commercially available Click-iT ethynyl-deoxyuridine cell proliferation kit to visualize the DNA replication sites of wild-typeArabidopsis thalianaseedlings, as well asfasciata1andnucleolin1plants and apply our in-section CLEM imaging workflow for the analysis of S-phase progression and nucleolar organization in mutant plants with aberrant nucleolar phenotypes.
The influence of cortical activity on perception depends on behavioral state and sensory context
Authors: Russell Lloyd E. , Fişek Mehmet , Yang Zidan , Tan Lynn Pei , Packer Adam M. , Dalgleish Henry W. P. , Chettih Selmaan N. , Harvey Christopher D. , Häusser Michael
Published: March 2024

The mechanistic link between neural circuit activity and behavior remains unclear. While manipulating cortical activity can bias certain behaviors and elicit artificial percepts, some tasks can still be solved when cortex is silenced or removed. Here, mice were trained to perform a visual detection task during which we selectively targeted groups of visually responsive and co-tuned neurons in L2/3 of primary visual cortex (V1) for two-photon photostimulation. The influence of photostimulation was conditional on two key factors: the behavioral state of the animal and the contrast of the visual stimulus. The detection of low-contrast stimuli was enhanced by photostimulation, while the detection of high-contrast stimuli was suppressed, but crucially, only when mice were highly engaged in the task. When mice were less engaged, our manipulations of cortical activity had no effect on behavior. The behavioral changes were linked to specific changes in neuronal activity. The responses of non-photostimulated neurons in the local network were also conditional on two factors: their functional similarity to the photostimulated neurons and the contrast of the visual stimulus. Functionally similar neurons were increasingly suppressed by photostimulation with increasing visual stimulus contrast, correlating with the change in behavior. Our results show that the influence of cortical activity on perception is not fixed, but dynamically and contextually modulated by behavioral state, ongoing activity and the routing of information through specific circuits.
The bone ecosystem facilitates multiple myeloma relapse and the evolution of heterogeneous drug resistant disease
Authors: Bishop Ryan T. , Miller Anna K. , Froid Matthew , Nerlakanti Niveditha , Li Tao , Frieling Jeremy S. , Nasr Mostafa M. , Nyman Karl J. , Sudalagunta Praneeth R. , Canevarolo Rafael R. , Silva Ariosto Siqueira , Shain Kenneth H. , Lynch Conor C. , Basanta David
Published: March 2024

Multiple myeloma (MM) is an osteolytic malignancy that is incurable due to the emergence of treatment resistant disease. Defining how, when and where myeloma cell intrinsic and extrinsic bone microenvironmental mechanisms cause relapse is challenging with current biological approaches. Here, we report a biology-driven spatiotemporal hybrid agent-based model of the MM-bone microenvironment. Results indicate MM intrinsic mechanisms drive the evolution of treatment resistant disease but that the protective effects of bone microenvironment mediated drug resistance (EMDR) significantly enhances the probability and heterogeneity of resistant clones arising under treatment. Further, the model predicts that targeting of EMDR deepens therapy response by eliminating sensitive clones proximal to stroma and bone, a finding supported by in vivo studies. Altogether, our model allows for the study of MM clonal evolution over time in the bone microenvironment and will be beneficial for optimizing treatment efficacy so as to significantly delay disease relapse.
Structure of orthoreovirus RNA chaperone σNS, a component of viral replication factories
Authors: Zhao Boyang , Hu Liya , Kaundal Soni , Neetu Neetu , Lee Christopher H. , Somoulay Xayathed , Sankaran Banumathi , Taylor Gwen M. , Dermody Terence S. , Venkataram Prasad B. V.
Published: March 2024

The mammalian orthoreovirus (reovirus) σNS protein is required for formation of replication compartments that support viral genome replication and capsid assembly. Despite its functional importance, a mechanistic understanding of σNS is lacking. We conducted structural and biochemical analyses of a σNS mutant that forms dimers instead of the higher-order oligomers formed by wildtype (WT) σNS. The crystal structure shows that dimers interact with each other using N-terminal arms to form a helical assembly resembling WT σNS filaments in complex with RNA observed using cryo-EM. The interior of the helical assembly is of appropriate diameter to bind RNA. The helical assembly is disrupted by bile acids, which bind to the same site as the N-terminal arm. This finding suggests that the N-terminal arm functions in conferring context-dependent oligomeric states of σNS, which is supported by the structure of σNS lacking an N-terminal arm. We further observed that σNS has RNA chaperone activity likely essential for presenting mRNA to the viral polymerase for genome replication. This activity is reduced by bile acids and abolished by N-terminal arm deletion, suggesting that the activity requires formation of σNS oligomers. Our studies provide structural and mechanistic insights into the function of σNS in reovirus replication.
Two DOT1 enzymes cooperatively mediate efficient ubiquitin-independent histone H3 lysine 76 tri-methylation in kinetoplastids
Authors: Frisbie Victoria S. , Hashimoto Hideharu , Xie Yixuan , De Luna Vitorino Francisca N. , Baeza Josue , Nguyen Tam , Yuan Zhangerjiao , Kiselar Janna , Garcia Benjamin A. , Debler Erik W.
Published: March 2024

In higher eukaryotes, a single DOT1 histone H3 lysine 79 (H3K79) methyltransferase processively produces H3K79me2/me3 through histone H2B mono-ubiquitin interaction, while the kinetoplastid Trypanosoma brucei di-methyltransferase DOT1A and tri-methyltransferase DOT1B efficiently methylate the homologous H3K76 without H2B mono-ubiquitination. Based on structural and biochemical analyses of DOT1A, we identify key residues in the methyltransferase motifs VI and X for efficient ubiquitin-independent H3K76 methylation in kinetoplastids. Substitution of a basic to an acidic residue within motif VI (Gx6K) is essential to stabilize the DOT1A enzyme-substrate complex, while substitution of the motif X sequence VYGE by CAKS renders a rigid active-site loop flexible, implying a distinct mechanism of substrate recognition. We further reveal distinct methylation kinetics and substrate preferences of DOT1A (H3K76me0) and DOT1B (DOT1A products H3K76me1/me2) in vitro, determined by a Ser and Ala residue within motif IV, respectively, enabling DOT1A and DOT1B to mediate efficient H3K76 tri-methylation non-processively but cooperatively, and suggesting why kinetoplastids have evolved two DOT1 enzymes.
Legionella metaeffector MavL reverses ubiquitin ADP-ribosylation via a conserved arginine-specific macrodomain
Authors: Zhang Zhengrui , Fu Jiaqi , Rack Johannes Gregor Matthias , Li Chuang , Voorneveld Jim , Filippov Dmitri V. , Ahel Ivan , Luo Zhao-Qing , Das Chittaranjan
Published: March 2024

ADP-ribosylation is a reversible post-translational modification involved in various cellular activities. Removal of ADP-ribosylation requires (ADP-ribosyl)hydrolases, with macrodomain enzymes being a major family in this category. The pathogen Legionella pneumophila mediates atypical ubiquitination of host targets using the SidE effector family in a process that involves ubiquitin ADP-ribosylation on arginine 42 as an obligatory step. Here, we show that the Legionella macrodomain effector MavL regulates this pathway by reversing the arginine ADP-ribosylation, likely to minimize potential detrimental effects caused by the modified ubiquitin. We determine the crystal structure of ADP-ribose-bound MavL, providing structural insights into recognition of the ADP-ribosyl group and catalytic mechanism of its removal. Further analyses reveal DUF4804 as a class of MavL-like macrodomain enzymes whose representative members show unique selectivity for mono-ADP-ribosylated arginine residue in synthetic substrates. We find such enzymes are also present in eukaryotes, as exemplified by two previously uncharacterized (ADP-ribosyl)hydrolases in Drosophila melanogaster. Crystal structures of several proteins in this class provide insights into arginine specificity and a shared mode of ADP-ribose interaction distinct from previously characterized macrodomains. Collectively, our study reveals a new regulatory layer of SidE-catalyzed ubiquitination and expands the current understanding of macrodomain enzymes.
Elevated blood remnant cholesterol and triglycerides are causally related to the risks of cardiometabolic multimorbidity
Authors: Zhao Yimin , Zhuang Zhenhuang , Li Yueying , Xiao Wendi , Song Zimin , Huang Ninghao , Wang Wenxiu , Dong Xue , Jia Jinzhu , Clarke Robert , Huang Tao
Published: March 2024

The connection between triglyceride-rich lipoproteins and cardiometabolic multimorbidity, characterized by the concurrence of at least two of type 2 diabetes, ischemic heart disease, and stroke, has not been definitively established. We aim to examine the prospective associations between serum remnant cholesterol, triglycerides, and the risks of progression from first cardiometabolic disease to multimorbidity via multistate modeling in the UK Biobank. We also evaluate the causality of these associations via Mendelian randomization using 13 biologically relevant SNPs as the genetic instruments. Here we show that elevated remnant cholesterol and triglycerides are significantly associated with gradually higher risks of cardiometabolic multimorbidity, particularly the progression of ischemic heart disease to the multimorbidity of ischemic heart disease and type 2 diabetes. These results advocate for effective management of remnant cholesterol and triglycerides as a potential strategy in mitigating the risks of cardiometabolic multimorbidity.