bluuebunny/crossref_metadata_2025 huggingface dataset:
The Selection and Tenure of Foreign Ministers Around the World
Authors: Bäck Hanna , Flores Alejandro Quiroz , Teorell Jan
Published: February 2024

Foreign ministers are prominent actors in foreign affairs, often second only to heads of government in their influence. Yet, despite the growing awareness of the importance of key actors, and their backgrounds, in the study of international relations, foreign ministers remain understudied. In this Element, we make an important empirical contribution by presenting an original dataset on the personal and professional background of foreign ministers, spanning thirteen countries and more than 200 years. We use these data to answer three questions: who are the foreign ministers, why are foreign ministers with particular features appointed, and why do some foreign ministers have longer tenure than others? We find that foreign ministers tend to be men of politics who are appointed both on the basis of their affinity to, and to complement the experiences of, the head of government. We also find that foreign ministers stay longer in office when they perform well or are expected to do so, but that they are more likely to lose their posts when conditions make heads of government more prone to 'pin blame' on them to deflect criticism from foreign policy failures.
Classification of English vowels in terms of Cypriot Greek categories: The role of acoustic similarity between L1 and L2 sounds
Authors: Georgiou Georgios P.
Published: February 2024

Previous evidence has suggested that acoustic similarity between first language (L1) and second language (L2) sounds is an accurate indicator of the speakers’ L2 classification patterns. This study investigates this assumption by examining how speakers of an under-researched language, namely Cypriot Greek, classify L2 English vowels in terms of their L1 categories. The experimental protocol relied on a perception and a production study. For the purpose of the production study, two linear discriminant analysis (LDA) models, one with both formants and duration (FD) and one with only formants (F) as input, were used to predict this classification; the models included data from both English and Cypriot Greek speakers. The perception study consisted of a classification task performed by adult Cypriot Greek advanced speakers of English who permanently resided in Cyprus. The results demonstrated that acoustic similarity was a relatively good predictor of speakers’ classification patterns as the majority of L2 vowels classified with the highest proportion were predicted with success by the LDA models. In addition, the F model was better than the FD model in predicting the full range of responses. This shows that duration features were less important than formant features for the prediction of L2 vowel classification.
RECONSTRUCTING THE CHRONOLOGY OF BUILDING THE SOUTHWEST CHURCH OF UMM EL-JIMAL, JORDAN BY AMS RADIOCARBON DATING OF MORTAR AND PLASTER
Authors: Al-Bashaireh Khaled
Published: February 2024

The research aims to reconstruct the chronology of building the Southwest Church, Umm el-Jimal, Jordan by AMS radiocarbon dating organic inclusions uncovered from the mortars collected from the floor of the church, seat of the apse and the base of the north wall. It sheds light on the major aspects of mortar recipes at the time of their production. Samples were examined macroscopically with magnifying lenses and characterized using archaeometric techniques of optical microscopy and X-ray diffraction. The radiocarbon dates showed that 594–643 AD is the most probable age for flooring and plastering the church and 995–1154 AD is the earliest possible date for its final collapse. The preparatory layers of the church floor were laid on an older one, probably of a yard, and its north wall was raised on an older base, both most probably date to the late fifth–early sixth century AD. The production recipe of the mortars is made from a lime binder and inclusions mainly of organic (charcoal) and inorganic (quartz, grog, volcanics). The mortars have the same recipe regardless their bedding and jointing functions which remained unchanged during the building stages of church complex.
Egg white hydrolysate protects white adipose tissue against metabolic insult in deoxycorticosterone acetate-salt rats
Authors: Rodrigues Moro Camila , Abreu Edina da Luz , Kanaan Samia Hassan Husein , Márquez Antonio , Uranga-Ocio Jose Antonio , Rossoni Luciana Venturini , Vassallo Dalton Valentim , Miguel-Castro Marta , Wiggers Giulia Alessandra
Published: February 2024

The purpose of this study was to investigate the effect of an egg white hydrolysate (EWH) to protect white adipose tissue damage from cardiometabolic changes induced by severe hypertension. Male Wistar rats were uninephrectomised and divided: SHAM (weekly subcutaneous vehicle (mineral oil + propylene glycol, 1:1)), SHAM + EWH (subcutaneous vehicle plus EWH via gavage, 1 g/kg per day), DOCA (deoxycorticosterone acetate diluted in vehicle subcutaneously weekly in subsequent doses of 20 mg/kg -1st week, 12 mg/kg - 2–3th week, and 6 mg/kg -4–8th week, respectively, plus 1 % NaCl and 0·2 % KCl in drinking water), and DOCA + EWH. Body weight gain, food and water intake, glucose and lipid metabolism were evaluated. Oxidative stress was assessed by biochemical assay and immunofluorescence for NOX-1, nuclear factor kappa B (NFκB), and caspase-3 in retroperitoneal white adipose tissue (rtWAT). Proinflammatory cytokines (IL-6 and 1β), CD163+ macrophage infiltration, and immunohistochemistry for TNFα and uncoupling protein-1 were evaluated, as well as histological analysis on rtWAT. Glutathione peroxidase and reductase were also determined in plasma. EWH showed hypocholesterolemic, antioxidant, anti-inflammatory, and anti-apoptotic properties in the arterial hypertension DOCA-salt model. The results demonstrated the presence of functional changes in adipose tissue function by a decrease in macrophage infiltration and in the fluorescence intensity of NFκB, NOX-1, and caspase-3. A reduction of proinflammatory cytokines and restoration of antioxidant enzymatic activity and mitochondrial oxidative damage by reducing uncoupling protein-1 fluorescence intensity were also observed. EWH could be used as a potential alternative therapeutic strategy in the treatment of cardiometabolic complications associated with malignant secondary arterial hypertension.
Magnetic fields with general omnigenity
Authors: Dudt Daniel W. , Goodman Alan G. , Conlin Rory , Panici Dario , Kolemen Egemen
Published: February 2024

Omnigenity is a desirable property of toroidal magnetic fields that ensures confinement of trapped particles. Confining charged particles is a basic requirement for any fusion power plant design, but it can be difficult to satisfy with the non-axisymmetric magnetic fields used by the stellarator approach. Every ideal magnetohydrodynamic equilibrium previously found to approximate omnigenity has been either axisymmetric, quasi-symmetric or has poloidally closed contours of magnetic field strength

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. However, general omnigenous equilibria are a much larger design space than these subsets. A new model is presented and employed in the DESC stellarator optimization suite to represent and discover the full parameter space of omnigenous equilibria. Although exact omnigenity aside from quasi-symmetry is impossible, these results reveal that excellent particle confinement can be achieved in practice. Examples far from quasi-symmetry with poloidally, helically and toroidally closed

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contours are attained with DESC and shown to have low neoclassical collisional transport and fast particle losses.
Aortic dilation in adults with repaired tetralogy of Fallot: a single-centre study
Authors: Saedi Tahereh , Siami Rashide , Ghaffari Amir J. , Farmani Danial , Saedi Sedigheh
Published: February 2024

Background:

Tetralogy of Fallot is the most prevalent cyanotic CHD. With the advent of advanced surgical methods, the majority of tetralogy of Fallot patients reach adulthood. However, many need re-intervention for the residual anomalies including residual right ventricular outflow obstruction, pulmonary regurgitation, residual ventricular septal defects, and progressive aortic dilatation. Aortic dilation could lead to aortic regurgitation or dissection requiring surgical correction. In the current study, we aimed to determine the prevalence and outcomes of aortic root dilatation in adults with repaired tetralogy of Fallot in our tertiary care centre.

Methods:

In this retrospective study, 730 consecutive patients with history of repaired tetralogy of Fallot were included. Aortic diameter at the level of annulus, the sinus of Valsalva, sinotubular junction, and the ascending aorta as measured by echocardiography were evaluated. Prevalence of outcomes necessitating re-intervention including aortic regurgitation and dissection were recorded.

Results:

The mean size of annulus, sinus of Valsalva, sinotubular-junction, and ascending aorta in the latest available echocardiography of patients were 2.4+/-0.4 cm, 3.3+/-0.5 cm, 2.9+/-0.5cm, and 3.2+/-0.5cm, respectively. Prevalence of dilatation of sinus of Valsalva, dilation of Ascending aorta, sinotubular-junction, and aortic annulus was 28.7%, 21%, 8.3%, and 1 %, respectively. Five patients had severe aortic regurgitation (0.6%) and underwent surgical repair. One of these patients presented with acute aortic dissection.

Conclusion:

Aortic dilation is common in tetralogy of Fallot but prevalence of redo surgery for aortic dilation, regurgitation, and adverse events including acute dissection is low.
Heterogeneities in Regional Air Pollutant Emission Mitigation Across China During 2012–2020
Authors: Zhao Hongyan , He Wenjie , Cheng Jing , Liu Yang , Zheng Yixuan , Tian Hezhong , He Kebin , Lei Yu , Zhang Qiang
Published: February 2024

The toughest‐ever clean air actions to date in China have helped to reduce national air pollutant emissions significantly in recent years. However, the heterogeneous mitigation paths and their determinated factors among regions were less concerned. To direct regional mitigation strategies more efficiently, we compiled a time‐series emission inventory of Chinese 30 provinces for SO2, NOx, primary PM2.5 and CO2 at detailed socioeconomic sectors, and then used spatial‐temporal index decomposition analysis to evaluate the driving forces for changes in regional pollutant emissions and emission intensities from 2012 to 2017 and from 2017 to 2020, separately. Our results showed that end‐of‐pipe control measures dominated the decreasing trend of China's pollutant emissions (38%–68% for SO2, NOx, and primary PM2.5), but their relative dominance diminished gradually, and the effects from energy policy emerged, even outweighing the former in southern areas during the second phase. Though driven by different factors, the chemistry, nonmetal, metal, energy and residential sectors dominated regional reduction trend and with varying degrees. Clean air action led to the convergence of regional emission intensity, while optimizing and upgrading industrial structure and improving energy efficiency is still necessary for further reduction in northern and western areas at present.
The Impact of Assimilating Cirrus‐Effected Infrared Satellite Radiance From the FY‐4A AGRI on Water Vapor Analysis and Rainstorm Forecasting
Authors: Xu Lan , Liu Juanjuan , Cheng Wei , Wang Shudong , Zhu Shujun , He Yujun , Liu Yiran , Shen Xiao , Wang Jing , Fu Jinrong , Jiao Yifeng , Ma Yuanzhe , Wang Bin
Published: February 2024

In this study, a method for assimilating FY4A advanced geostationary radiance imager (AGRI) cirrus‐effected radiances (CER) is investigated, and the impact of this method on water vapor analysis and rainstorm forecasting is examined through observing system simulation experiments and actual case experiments. The high proportion of inverted humidity profiles in the cirrus‐effected pixels is the main reason for the negative effect of assimilation in the mid‐to‐lower troposphere. To address this, relevant constraint conditions are incorporated into the cost function. The statistical results reveal that the addition of a CER assimilation improves the analysis increment of water vapor, with pattern correlation coefficients of 0.33, 0.35, and 0.20 at 200, 300, and 400 hPa, respectively, which are greater than those of a clear‐sky radiance assimilation (0.28, 0.33, and 0.17, respectively). Moreover, the inclusion of a CER assimilation greatly improves data utilization, and has a neutral to positive effect on precipitation forecasting.
Signature of Sudden Stratospheric Warming in the Pole and Its Antipode
Authors: Dutta Reetambhara , Sridharan S. , Sinha P. R.
Published: February 2024

In this study, the boreal sudden stratospheric warming (SSW) event of 2013 and the austral SSW event of 2019 are considered to investigate the influence of the SSW events on the polar and antipodal upper mesosphere and lower thermosphere (UMLT) regions using ground‐based, space‐borne, reanalysis and model data sets. During the SSW events, the solar semi‐diurnal tidal (SDT) amplitudes are much larger than the lunar amplitudes in both UMLT regions. Besides, the solar SDT shows an increase in its amplitude in both the polar UMLT heights during the SSW events. However, the lunar tides show enhancement in its amplitude in the boreal polar UMLT region during both the SSW events. In the antipodal UMLT region, a peak enhancement in solar SDT amplitude is observed a few days after the onset of the boreal SSW and near to the onset time of the austral SSW. No concurrent stratospheric ozone volume mixing ratio (vmr) increase is observed which indicates that the SDT peak can be unlikely due to the underlying stratospheric ozone vmr changes. However, similar periodicity in the UMLT zonal winds of both poles indicates the possibility of cross equatorial propagation of planetary wave (PW). As the SDT amplitude also reveal similar planetary wave periodicity as observed in zonal wind, it is suggested that the PW modulation of the SDT could be the reason for the enhancement of SDT in the opposite polar UMLT region.
Physical and Biogeochemical Properties of California Current Upwelled Source Waters
Authors: Fiechter Jerome , Moore Andrew M.
Published: February 2024

Coastal upwelling variability in the California Current region, one of the four main eastern boundary current upwelling systems, is controlled by processes acting over a wide range of spatial and temporal scales. While the ensuing ecosystem response depends strongly on upwelled water properties, determining their exact physical and biogeochemical characteristics is notoriously difficult as it requires tracking water masses backward in space and time from the moment they upwell near the coast to their subsurface origin. Adjoint model simulations have been used successfully to track water masses in coastal upwelling systems and the work presented here extends these applications to determining the co‐variability of physical and biogeochemical properties of source waters at spatial scales that resolve the known alongshore variability of coastal upwelling in the region. Notably, the results identify that the modulation of coastal upwelling efficiency by onshore/offshore geostrophic meanders is the dominant mechanism explaining alongshore variability in source depth and properties of upwelled waters. The simulations also reveal that source water properties vary seasonally in response to different balances between coastal upwelling intensity and biogeochemical processes. During spring, interannual variability of physical and biogeochemical properties is directly tied to the intensity of upwelling‐favorable alongshore winds, whereas, during summer, biogeochemical properties respond more strongly to biological activity and subsequent organic matter remineralization at depth. Overall, the present work provides important insight into the mechanisms responsible for the alongshore mosaic and seasonal variation of upwelled source water properties in the central California Current region.
Evolution of Impact Melt Pools on Titan
Authors: Kalousová Klára , Wakita Shigeru , Sotin Christophe , Neish Catherine D. , Soderblom Jason M. , Souček Ondřej , Johnson Brandon C.
Published: February 2024

Titan is an ocean world with a dense atmosphere, where photochemistry produces complex organic molecules that fall to the surface. An important astrobiological question is whether this material can mix with water and form molecules of biological interest. Large impacts heat the moon's subsurface and create liquid water melt pools. A recent study investigated impacts into Titan's clathrate‐covered ice shell. Methane clathrates are stable at Titan's surface conditions and have low thermal conductivity, making them efficient insulators that can lead to steep thermal gradients and a thin stagnant lid. The authors showed that the clathrate layer thickness primarily influences the melt distribution, while its volume is governed by the impactor size. Here, we investigate the fate of melt formed during an impact into a clathrate‐covered ice shell. Our results show two different behaviors: in cases when less melt is produced, the subsurface melt pool remains close to the surface and freezes on timescales ≲25 kyr; in cases when larger volumes of melt are produced, a downward‐oriented transport of the molten material occurs. As it descends, part of the melt freezes but some may reach the ocean within a few kyr under certain conditions; vertical impacts, high surface porosity, low viscosity, and tidal heating all favor this surface‐to‐ocean exchange. While providing insights on parameters that allow a subsurface melt pool to remain liquid beneath a Selk‐sized crater for a few kyr, this study suggests that Dragonfly may be able to sample melt deposits where organics reacted with liquid water to produce biomolecules.
Quantification of the Airborne Fraction of Atmospheric CO2 Reveals Stability in Global Carbon Sinks Over the Past Six Decades
Authors: Bennett Brian F. , Salawitch Ross J. , McBride Laura A. , Hope Austin P. , Tribett Walter R.
Published: February 2024

The airborne fraction of atmospheric CO2 (AF), defined as the annual global CO2 growth rate (dCO2/dt) divided by the total emission of CO2 from combustion of fossil fuels and land use change (LUC), has a long‐term average of ∼0.44 over the past six decades. When quantifying trends in AF it is important to account for inter‐annual variability in dCO2/dt due to natural factors such as the El Niño Southern Oscillation (ENSO) and major volcanic eruptions, as well as assumptions regarding LUC. Here, a multiple linear regression model is used to compute dCO2/dt as a function of anthropogenic CO2 emissions, ENSO indices, and stratospheric aerosol optical depth (a proxy for major volcanic eruptions), for numerous time series of the emission of CO2 due to LUC (ELUC). For 20 out of 21 previously published ELUC time series, the trend in AF adjusted for natural variability (AFADJ) over 1959 to 2021 exhibits a trend that is statistically indistinguishable from zero and lacks statistical significance at the 95% confidence interval. Therefore, it is most likely that the relative efficacy of the combined global terrestrial biosphere and oceanic carbon sinks has been fairly constant on a global scale over the past six decades. Since the trend in AF exhibits considerable variability depending on which ELUC time series is used, more precise knowledge of the actual value of the AF trend will require resolving the current large differences in various estimates of ELUC.
El Ni�o May Have Kicked Off Thwaites Glacier Retreat
Authors: van Deelen Grace
Published: February 2024

Antarctica’s “Doomsday Glacier” started losing mass midcentury, around the same time as its neighboring glacier.
Nightmares share genetic risk factors with sleep and psychiatric traits
Authors: Ollila Hanna M. , Sinnott-Armstrong Nasa , Kantojärvi Katri , Broberg Martin , Palviainen Teemu , Jones Samuel , Ripatti Vili , Pandit Anita , Rong Robin , Kristiansson Kati , Sandman Nils , Valli Katja , Hublin Christer , Ripatti Samuli , Widen Elisabeth , Kaprio Jaakko , Saxena Richa , Paunio Tiina
Published: February 2024

Nightmares are vivid, extended, and emotionally negative or negative dreams that awaken the dreamer. While sporadic nightmares and bad dreams are common and generally harmless, frequent nightmares often reflect underlying pathologies of emotional regulation. Indeed, insomnia, depression, anxiety, or alcohol use have been associated with nightmares in epidemiological and clinical studies. However, the connection between nightmares and their comorbidities are poorly understood. Our goal was to examine the genetic risk factors for nightmares and estimate correlation or causality between nightmares and comorbidities. We performed a genome-wide association study (GWAS) in 45,255 individuals using a questionnaire-based assessment on the frequency of nightmares during the past month and genome-wide genotyping data. While the GWAS did not reveal individual risk variants, heritability was estimated at 5%. In addition, the genetic correlation analysis showed a robust correlation (rg > 0.4) of nightmares with anxiety (rg = 0.671, p = 7.507e−06), depressive (rg = 0.562, p = 1.282e−07) and posttraumatic stress disorders (rg = 0.4083, p = 0.0152), and personality trait neuroticism (rg = 0.667, p = 4.516e−07). Furthermore, Mendelian randomization suggested causality from insomnia to nightmares (beta = 0.027, p = 0.0002). Our findings suggest that nightmares share genetic background with psychiatric traits and that insomnia may increase an individual’s liability to experience frequent nightmares. Given the significant correlations with psychiatric and psychological traits, it is essential to grow awareness of how nightmares affect health and disease and systematically collect information about nightmares, especially from clinical samples and larger cohorts.
KEAP1 promotes anti-tumor immunity by inhibiting PD-L1 expression in NSCLC
Authors: Li Jinghan , Shi Daiwang , Li Siyi , Shi Xiang , Liu Yu , Zhang Yi , Wang Gebang , Zhang Chenlei , Xia Tian , Piao Hai-long , Liu Hong-Xu
Published: February 2024

Immunotherapy has become a prominent first-line cancer treatment strategy. In non-small cell lung cancer (NSCLC), the expression of PD-L1 induces an immuno-suppressive effect to protect cancer cells from immune elimination, which designates PD-L1 as an important target for immunotherapy. However, little is known about the regulation mechanism and the function of PD-L1 in lung cancer. In this study, we have discovered that KEAP1 serves as an E3 ligase to promote PD-L1 ubiquitination and degradation. We found that overexpression of KEAP1 suppressed tumor growth and promoted cytotoxic T-cell activation in vivo. These results indicate the important role of KEAP1 in anti-cancer immunity. Moreover, the combination of elevated KEAP1 expression with anti-PD-L1 immunotherapy resulted in a synergistic effect on both tumor growth and cytotoxic T-cell activation. Additionally, we found that the expressions of KEAP1 and PD-L1 were associated with NSCLC prognosis. In summary, our findings shed light on the mechanism of PD-L1 degradation and how NSCLC immune escape through KEAP1-PD-L1 signaling. Our results also suggest that KEAP1 agonist might be a potential clinical drug to boost anti-tumor immunity and improve immunotherapies in NSCLC.
SNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation
Authors: Nashabat Marwan , Nabavizadeh Nasrinsadat , Saraçoğlu Hilal Pırıl , Sarıbaş Burak , Avcı Şahin , Börklü Esra , Beillard Emmanuel , Yılmaz Elanur , Uygur Seyide Ecesu , Kayhan Cavit Kerem , Bosco Luca , Eren Zeynep Bengi , Steindl Katharina , Richter Manuela Friederike , Bademci Guney , Rauch Anita , Fattahi Zohreh , Valentino Maria Lucia , Connolly Anne M. , Bahr Angela , Viola Laura , Bergmann Anke Katharina , Rocha Maria Eugenia , Peart LeShon , Castro-Rojas Derly Liseth , Bültmann Eva , Khan Suliman , Giarrana Miriam Liliana , Teleanu Raluca Ioana , Gonzalez Joanna Michelle , Pini Antonella , Schädlich Ines Sophie , Vill Katharina , Brugger Melanie , Zuchner Stephan , Pinto Andreia , Donkervoort Sandra , Bivona Stephanie Ann , Riza Anca ,   Undiagnosed Diseases Network, Zuchner Stephan , Tekin Mustafa , Streata Ioana , Gläser Dieter , Baquero-Montoya Carolina , Garcia-Restrepo Natalia , Kotzaeridou Urania , Brunet Theresa , Epure Diana Anamaria , Bertoli-Avella Aida , Kariminejad Ariana , Tekin Mustafa , von Hardenberg Sandra , Bönnemann Carsten G. , Stettner Georg M. , Zanni Ginevra , Kayserili Hülya , Oflazer Zehra Piraye , Escande-Beillard Nathalie
Published: February 2024

SNURPORTIN-1, encoded by SNUPN, plays a central role in the nuclear import of spliceosomal small nuclear ribonucleoproteins. However, its physiological function remains unexplored. In this study, we investigate 18 children from 15 unrelated families who present with atypical muscular dystrophy and neurological defects. Nine hypomorphic SNUPN biallelic variants, predominantly clustered in the last coding exon, are ascertained to segregate with the disease. We demonstrate that mutant SPN1 failed to oligomerize leading to cytoplasmic aggregation in patients’ primary fibroblasts and CRISPR/Cas9-mediated mutant cell lines. Additionally, mutant nuclei exhibit defective spliceosomal maturation and breakdown of Cajal bodies. Transcriptome analyses reveal splicing and mRNA expression dysregulation, particularly in sarcolemmal components, causing disruption of cytoskeletal organization in mutant cells and patient muscle tissues. Our findings establish SNUPN deficiency as the genetic etiology of a previously unrecognized subtype of muscular dystrophy and provide robust evidence of the role of SPN1 for muscle homeostasis.
Comparative connectomics of dauer reveals developmental plasticity
Authors: Yim Hyunsoo , Choe Daniel T. , Bae J. Alexander , Choi Myung-kyu , Kang Hae-Mook , Nguyen Ken C. Q. , Ahn Soungyub , Bahn Sang-kyu , Yang Heeseung , Hall David H. , Kim Jinseop S. , Lee Junho
Published: February 2024

A fundamental question in neurodevelopmental biology is how flexibly the nervous system changes during development. To address this, we reconstructed the chemical connectome of dauer, an alternative developmental stage of nematodes with distinct behavioral characteristics, by volumetric reconstruction and automated synapse detection using deep learning. With the basic architecture of the nervous system preserved, structural changes in neurons, large or small, were closely associated with connectivity changes, which in turn evoked dauer-specific behaviors such as nictation. Graph theoretical analyses revealed significant dauer-specific rewiring of sensory neuron connectivity and increased clustering within motor neurons in the dauer connectome. We suggest that the nervous system in the nematode has evolved to respond to harsh environments by developing a quantitatively and qualitatively differentiated connectome.
TopBP1 utilises a bipartite GINS binding mode to support genome replication
Authors: Day Matthew , Tetik Bilal , Parlak Milena , Almeida-Hernández Yasser , Räschle Markus , Kaschani Farnusch , Siegert Heike , Marko Anika , Sanchez-Garcia Elsa , Kaiser Markus , Barker Isabel A. , Pearl Laurence H. , Oliver Antony W. , Boos Dominik
Published: February 2024

Activation of the replicative Mcm2-7 helicase by loading GINS and Cdc45 is crucial for replication origin firing, and as such for faithful genetic inheritance. Our biochemical and structural studies demonstrate that the helicase activator GINS interacts with TopBP1 through two separate binding surfaces, the first involving a stretch of highly conserved amino acids in the TopBP1-GINI region, the second a surface on TopBP1-BRCT4. The two surfaces bind to opposite ends of the A domain of the GINS subunit Psf1. Mutation analysis reveals that either surface is individually able to support TopBP1-GINS interaction, albeit with reduced affinity. Consistently, either surface is sufficient for replication origin firing in Xenopus egg extracts and becomes essential in the absence of the other. The TopBP1-GINS interaction appears sterically incompatible with simultaneous binding of DNA polymerase epsilon (Polε) to GINS when bound to Mcm2-7-Cdc45, although TopBP1-BRCT4 and the Polε subunit PolE2 show only partial competitivity in binding to Psf1. Our TopBP1-GINS model improves the understanding of the recently characterised metazoan pre-loading complex. It further predicts the coordination of three molecular origin firing processes, DNA polymerase epsilon arrival, TopBP1 ejection and GINS integration into Mcm2-7-Cdc45.
scCircle-seq unveils the diversity and complexity of extrachromosomal circular DNAs in single cells
Authors: Chen Jinxin Phaedo , Diekmann Constantin , Wu Honggui , Chen Chong , Della Chiara Giulia , Berrino Enrico , Georgiadis Konstantinos L. , Bouwman Britta A. M. , Virdi Mohit , Harbers Luuk , Bellomo Sara Erika , Marchiò Caterina , Bienko Magda , Crosetto Nicola
Published: February 2024

Extrachromosomal circular DNAs (eccDNAs) have emerged as important intra-cellular mobile genetic elements that affect gene copy number and exert in trans regulatory roles within the cell nucleus. Here, we describe scCircle-seq, a method for profiling eccDNAs and unraveling their diversity and complexity in single cells. We implement and validate scCircle-seq in normal and cancer cell lines, demonstrating that most eccDNAs vary largely between cells and are stochastically inherited during cell division, although their genomic landscape is cell type-specific and can be used to accurately cluster cells of the same origin. eccDNAs are preferentially produced from chromatin regions enriched in H3K9me3 and H3K27me3 histone marks and are induced during replication stress conditions. Concomitant sequencing of eccDNAs and RNA from the same cell uncovers the absence of correlation between eccDNA copy number and gene expression levels, except for a few oncogenes, including MYC, contained within a large eccDNA in colorectal cancer cells. Lastly, we apply scCircle-seq to one prostate cancer and two breast cancer specimens, revealing cancer-specific eccDNA landscapes and a higher propensity of eccDNAs to form in amplified genomic regions. scCircle-seq is a scalable tool that can be used to dissect the complexity of eccDNAs across different cell and tissue types, and further expands the potential of eccDNAs for cancer diagnostics.
How heat propagates in liquid 3He
Authors: Behnia Kamran , Trachenko Kostya
Published: February 2024

In Landau’s Fermi liquid picture, transport is governed by scattering between quasi-particles. The normal liquid 3He conforms to this picture but only at very low temperature. Here, we show that the deviation from the standard behavior is concomitant with the fermion-fermion scattering time falling below the Planckian time, $$\frac{\hslash }{{k}_{{{{{{{{\rm{B}}}}}}}}}T}$$

ℏ

k

B

T

and the thermal diffusivity of this quantum liquid is bounded by a minimum set by fundamental physical constants and observed in classical liquids. This points to collective excitations (a sound mode) as carriers of heat. We propose that this mode has a wavevector of 2kF and a mean free path equal to the de Broglie thermal length. This would provide an additional conducting channel with a T 1/2 temperature dependence, matching what is observed by experiments. The experimental data from 0.007 K to 3 K can be accounted for, with a margin of 10%, if thermal conductivity is the sum of two contributions: one by quasi-particles (varying as the inverse of temperature) and another by sound (following the square root of temperature).
Accelerated elastin degradation by age-disease interaction: a common feature in age-related diseases
Authors: Shek Naomi , Choy Anna-Maria , Lang Chim C. , Miller Bruce E. , Tal-Singer Ruth , Bolton Charlotte E. , Thomson Neil C. , Chalmers James D. , Bown Matt J. , Newby David E. , Khan Faisel , Huang Jeffrey T. J.
Published: February 2024

Aging is a major driving force for many diseases but the relationship between chronological age, the aging process and age-related diseases is not fully understood. Fragmentation and loss of ultra-long-lived elastin are key features in aging and several age-related diseases leading to increased mortality. By comparing the relationship between age and elastin turnover with healthy volunteers, we show that accelerated elastin turnover by age-disease interaction is a common feature of age-related diseases.
Thwarting resistance: MgrA inhibition with methylophiopogonanone a unveils a new battlefront against S. aureus
Authors: Guo Xuerui , Wang Li , Zhang Jinlong , Liu Quan , Wang Bingmei , Liu Da , Gao Fei , Lanzi Gongga , Zhao Yicheng , Shi Yan
Published: February 2024

Limitations in the clinical treatment of Staphylococcus aureus (S. aureus) infections have arisen due to the advent of antibiotic-resistant strains. Given the immense potential of therapeutic strategies targeting bacterial virulence, the role of MgrA as a pivotal virulence determinant in S. aureus-orchestrating resistance, adherence, and hundreds of virulence targets—becomes indispensable. In this investigation, leveraging advanced virtual screening and fluorescence anisotropy assays, we discerned methylophiopogonanone A (Mo-A), a flavonoid derivative, as a potent disruptor of the MgrA-DNA interaction nexus. Subsequent analysis revealed that Mo-A effectively inhibits the expression of virulence factors such as Hla and Pvl in S. aureus and markedly reduces its adhesion capability to fibrinogen. On a cellular landscape, Mo-A exerts a mitigating influence on the deleterious effects inflicted by S. aureus USA300 on A549 cells. Furthermore, our data indicate that Mo-A downregulates the transcription of genes associated with immune evasion, such as nucleases (nuc), Staphylococcal Chemotaxis Inhibitory Protein (chips), and Staphylococcal Complement Inhibitor (scin), thereby undermining immune escape and amplifying neutrophil chemotaxis. Upon application in an in vivo setting, Mo-A assumes a protective persona in a murine model of S. aureus USA300-induced pneumonia and demonstrates efficacy in the Galleria mellonella infection model. Of note, S. aureus displayed no swift acquisition of resistance to Mo-A, and the effect was synergistically enhanced when used in combination with vancomycin. Our findings add substantive weight to the expanding field of virulence-targeted therapeutic strategies and set the stage for more comprehensive exploration of Mo-A potential in combating antibiotic-resistant S. aureus.
Linking cerebral hemodynamics and ocular microgravity-induced alterations through an in silico-in vivo head-down tilt framework
Authors: Fois Matteo , Diaz-Artiles Ana , Zaman Syeda Yasmin , Ridolfi Luca , Scarsoglio Stefania
Published: February 2024

Head-down tilt (HDT) has been widely proposed as a terrestrial analog of microgravity and used also to investigate the occurrence of spaceflight-associated neuro-ocular syndrome (SANS), which is currently considered one of the major health risks for human spaceflight. We propose here an in vivo validated numerical framework to simulate the acute ocular-cerebrovascular response to 6° HDT, to explore the etiology and pathophysiology of SANS. The model links cerebral and ocular posture-induced hemodynamics, simulating the response of the main cerebrovascular mechanisms, as well as the relationship between intracranial and intraocular pressure to HDT. Our results from short-term (10 min) 6° HDT show increased hemodynamic pulsatility in the proximal-to-distal/capillary-venous cerebral direction, a marked decrease (-43%) in ocular translaminar pressure, and an increase (+31%) in ocular perfusion pressure, suggesting a plausible explanation of the underlying mechanisms at the onset of ocular globe deformation and edema formation over longer time scales.
Electrodeposited graphene/layered double hydroxides micro/nanocontainers for both passive and active corrosion protection
Authors: Xu Teng , Wang Qian-Yu , Zhang Jin-Tao , Hu Ji-Ming
Published: February 2024

The poor dispersibility of layered double hydroxides (LDHs) is considered to be the main drawback limiting their application in anti-corrosive coatings. In this work, the problem is solved by combining LDHs with graphene (Gr). A facile electrochemically assisted deposition technique (EAT) is developed to prepare Gr/LDH micro/nano-containers. The high-barrier Gr and LDHs synergistically build a ‘labyrinth effect’ to lengthen the diffusion path of corrosive mediums. Moreover, corrosion inhibitors can be released from the interlayer galleries of LDHs and impede corrosion of metal substrate by substituting the aggressive ions. Therefore, the polyvinyl butyral (PVB) coatings doped with Gr/LDH micro/nano-containers pre-loaded with inhibitors 2-Mercaptobenzothiazole (MBT) have both passive and active corrosion protection properties and provide excellent protection to copper substrate.
Identification of 27 allele-specific regulatory variants in Parkinson’s disease using a massively parallel reporter assay
Authors: Farrow Sophie L. , Gokuladhas Sreemol , Schierding William , Pudjihartono Michael , Perry Jo K. , Cooper Antony A. , O’Sullivan Justin M.
Published: February 2024

Genome wide association studies (GWAS) have identified a number of genomic loci that are associated with Parkinson’s disease (PD) risk. However, the majority of these variants lie in non-coding regions, and thus the mechanisms by which they influence disease development, and/or potential subtypes, remain largely elusive. To address this, we used a massively parallel reporter assay (MPRA) to screen the regulatory function of 5254 variants that have a known or putative connection to PD. We identified 138 loci with enhancer activity, of which 27 exhibited allele-specific regulatory activity in HEK293 cells. The identified regulatory variant(s) typically did not match the original tag variant within the PD associated locus, supporting the need for deeper exploration of these loci. The existence of allele specific transcriptional impacts within HEK293 cells, confirms that at least a subset of the PD associated regions mark functional gene regulatory elements. Future functional studies that confirm the putative targets of the empirically verified regulatory variants will be crucial for gaining a greater understanding of how gene regulatory network(s) modulate PD risk.
Parkinson’s disease and schizophrenia interactomes contain temporally distinct gene clusters underlying comorbid mechanisms and unique disease processes
Authors: Karunakaran Kalyani B. , Jain Sanjeev , Brahmachari Samir K. , Balakrishnan N. , Ganapathiraju Madhavi K.
Published: February 2024

Genome-wide association studies suggest significant overlaps in Parkinson’s disease (PD) and schizophrenia (SZ) risks, but the underlying mechanisms remain elusive. The protein-protein interaction network (‘interactome’) plays a crucial role in PD and SZ and can incorporate their spatiotemporal specificities. Therefore, to study the linked biology of PD and SZ, we compiled PD- and SZ-associated genes from the DisGeNET database, and constructed their interactomes using BioGRID and HPRD. We examined the interactomes using clustering and enrichment analyses, in conjunction with the transcriptomic data of 26 brain regions spanning foetal stages to adulthood available in the BrainSpan Atlas. PD and SZ interactomes formed four gene clusters with distinct temporal identities (Disease Gene Networks or ‘DGNs’1-4). DGN1 had unique SZ interactome genes highly expressed across developmental stages, corresponding to a neurodevelopmental SZ subtype. DGN2, containing unique SZ interactome genes expressed from early infancy to adulthood, correlated with an inflammation-driven SZ subtype and adult SZ risk. DGN3 contained unique PD interactome genes expressed in late infancy, early and late childhood, and adulthood, and involved in mitochondrial pathways. DGN4, containing prenatally-expressed genes common to both the interactomes, involved in stem cell pluripotency and overlapping with the interactome of 22q11 deletion syndrome (comorbid psychosis and Parkinsonism), potentially regulates neurodevelopmental mechanisms in PD-SZ comorbidity. Our findings suggest that disrupted neurodevelopment (regulated by DGN4) could expose risk windows in PD and SZ, later elevating disease risk through inflammation (DGN2). Alternatively, variant clustering in DGNs may produce disease subtypes, e.g., PD-SZ comorbidity with DGN4, and early/late-onset SZ with DGN1/DGN2.
Changes in kynurenine metabolites in the gray and white matter of the dorsolateral prefrontal cortex of individuals affected by schizophrenia
Authors: Antenucci Nico , D’Errico Giovanna , Fazio Francesco , Nicoletti Ferdinando , Bruno Valeria , Battaglia Giuseppe
Published: February 2024

Alterations in the kynurenine pathway of tryptophan metabolism have been implicated in the pathophysiology of schizophrenia. Here, we performed an in-depth analysis of all metabolites of the kynurenine pathway, i.e., tryptophan (TRY), kynurenic acid (KYNA), L-kynurenine (KYN), 3-hydroxykynurenine (3-HK), anthranylic acid (ANA), 3-hydroxyanthranylic acid (3-HANA), xanthurenic acid (XA) and quinolinic acid (QUINA), in postmortem samples of the dorsolateral prefrontal cortex (DLPFC, Brodmann area 46, 9) of individuals affected by schizophrenia and non-schizophrenic controls. The analysis was carried out in the gray and white matter. Levels of KYN, 3-HK, ANA, and 3-HANA were significantly increased in both the gray and white matter of the DLPFC of individuals affected by schizophrenia, whereas levels of TRY, KYNA, and QUINA were increased exclusively in the white matter and remained unchanged in the gray matter. These increases in kynurenine metabolites did not correlate with age, sex, duration of the disease, and duration and type of antipsychotic medication. These findings suggest that the two major branches of the kynurenine pathway, i.e., the transamination of KYN into KYNA, and hydroxylation of KYN into 3-HK are activated in the white matter of individuals affected by schizophrenia, perhaps as a result of neuroinflammation, and support the evidence that abnormalities of the white matter are consistenly associated with schizophrenia.
Salmonellosis outbreak archive in China: data collection and assembly
Authors: Wang Zining , Huang Chenghu , Liu Yuhao , Chen Jiaqi , Yin Rui , Jia Chenghao , Kang Xiamei , Zhou Xiao , Liao Sihao , Jin Xiuyan , Feng Mengyao , Jiang Zhijie , Song Yan , Zhou Haiyang , Yao Yicheng , Teng Lin , Wang Baikui , Li Yan , Yue Min
Published: February 2024

Infectious disease outbreaks transcend the medical and public health realms, triggering widespread panic and impeding socio-economic development. Considering that self-limiting diarrhoea of sporadic cases is usually underreported, the Salmonella outbreak (SO) study offers a unique opportunity for source tracing, spatiotemporal correlation, and outbreak prediction. To summarize the pattern of SO and estimate observational epidemiological indicators, 1,134 qualitative reports screened from 1949 to 2023 were included in the systematic review dataset, which contained a 506-study meta-analysis dataset. In addition to the dataset comprising over 50 columns with a total of 46,494 entries eligible for inclusion in systematic reviews or input into prediction models, we also provide initial literature collection datasets and datasets containing socio-economic and climate information for relevant regions. This study has a broad impact on advancing knowledge regarding epidemic trends and prevention priorities in diverse salmonellosis outbreaks and guiding rational policy-making or predictive modeling to mitigate the infringement upon the right to life imposed by significant epidemics.
A modified generative adversarial networks with Yolov5 for automated forest health diagnosis from aerial imagery and Tabu search algorithm
Authors: Jayagopal Prabhu , Purushothaman Janaki Kumar , Mohan Prakash , Kondapaneni Upendra Babu , Periyasamy Jayalakshmi , Mathivanan Sandeep Kumar , Dalu Gemmachis Teshite
Published: February 2024

Our environment has been significantly impacted by climate change. According to previous research, insect catastrophes induced by global climate change killed many trees, inevitably contributing to forest fires. The condition of the forest is an essential indicator of forest fires. Analysis of aerial images of a forest can detect deceased and living trees at an early stage. Automated forest health diagnostics are crucial for monitoring and preserving forest ecosystem health. Combining Modified Generative Adversarial Networks (MGANs) and YOLOv5 (You Only Look Once version 5) is presented in this paper as a novel method for assessing forest health using aerial images. We also employ the Tabu Search Algorithm (TSA) to enhance the process of identifying and categorizing unhealthy forest areas. The proposed model provides synthetic data to supplement the limited labeled dataset, thereby resolving the frequent issue of data scarcity in forest health diagnosis tasks. This improvement enhances the model's ability to generalize to previously unobserved data, thereby increasing the overall precision and robustness of the forest health evaluation. In addition, YOLOv5 integration enables real-time object identification, enabling the model to recognize and pinpoint numerous tree species and potential health issues with exceptional speed and accuracy. The efficient architecture of YOLOv5 enables it to be deployed on devices with limited resources, enabling forest-monitoring applications on-site. We use the TSA to enhance the identification of unhealthy forest areas. The TSA method effectively investigates the search space, ensuring the model converges to a near-optimal solution, improving disease detection precision and decreasing false positives. We evaluated our MGAN-YOLOv5 method using a large dataset of aerial images of diverse forest habitats. The experimental results demonstrated impressive performance in diagnosing forest health automatically, achieving a detection precision of 98.66%, recall of 99.99%, F1 score of 97.77%, accuracy of 99.99%, response time of 3.543 ms and computational time of 5.987 ms. Significantly, our method outperforms all the compared target detection methods showcasing a minimum improvement of 2% in mAP.