bluuebunny/crossref_metadata_2025 huggingface dataset:
The Mopra Southern Galactic Plane CO Survey – data release 4– complete survey
Authors: Cubuk K. O. , Burton M. G. , Braiding C. , Wong G. F. , Rowell G. , Maxted N. I. , Eden D. , Alsaberi R. Z. E. , Blackwell R. , Enokiya R. , Feijen K. , Filipović M. D. , Freeman M. S. R. , Fujita S. , Ghavam M. , Gunay B. , Indermuehle B. , Hayashi K. , Kohno M. , Nagaya T. , Nishimura A. , Okawa K. , Rebolledo D. , Romano D. , Sano H. , Snoswell C. , Tothill N. F. H. , Tsuge K. , Voisin F. , Yamane Y. , Yoshiike S.
Published: August 2023

We present observations of the Mopra carbon monoxide (CO) survey of the Southern Galactic Plane, covering Galactic longitudes spanning

$l = 250^{\circ}$

(

$-110^{\circ}$

) to

$l = 355^{\circ}$

(

$-5^{\circ}$

), with a latitudinal coverage of at least

$|b|<1^\circ$

, totalling an area of

$>$

210 deg

$^{2}$

. These data have been taken at 0.6 arcmin spatial resolution and 0.1 km s

$^{-1}$

spectral resolution, providing an unprecedented view of the molecular gas clouds of the Southern Galactic Plane in the 109–115 GHz

$J = 1-0$

transitions of

$^{12}$

CO,

$^{13}$

CO, C

$^{18}$

O, and C

$^{17}$

O.
Introducing HiSCoD: A New Gateway for the Study of Historical Social Conflict
Authors: CHAMBRU CÉDRIC , MANEUVRIER-HERVIEU PAUL
Published: August 2023

The Historical Social Conflict Database (HiSCoD) is an ongoing project designed to provide to scholars and society at large with a set of resources for analyzing social conflict from the Middle Ages to the second half of the nineteenth century (c. 1000–c. 1870). Based on original archival research and existing repositories, the aim is to provide a global database of social conflict in past societies by collecting, aggregating, documenting, and harmonizing instances of conflict. As of today, the database contains data on more than twenty thousand events, from fiscal scuffles to urban revolts involving thousands of individuals. For every event, we provide information on the date, location, type of conflict, and, when possible, number of participants, participation of women, and a summary of events.
The impact of lexical specificity training on at-risk emergent bilinguals
Authors: Li Miao , Snow Catherine E. , Ely Lauren , Frijters Jan C. , Geva Esther , Chen Becky Xi
Published: August 2023

Emergent bilinguals (EBs) who are exposed to societal language at school but use another language at home may experience difficulties in mastering the societal language, especially those at risk for language and reading disabilities. Learning phonologically specific new words that discriminate between phonemes may foster phonological awareness and word reading. This study examined the effectiveness of a lexical specificity intervention program that targeted phoneme discrimination in EBs at risk for reading disabilities. EBs who scored below the 25th percentile on the screening measures were selected and randomly assigned to one of two conditions: at-risk intervention or at-risk control. Of the 76 EBs in the at-risk group, 40 were randomly assigned to receive the intervention. A group of 51 typically developing EBs who did not meet the risk criteria were selected as typical controls. The pre- and post-tests include phoneme discrimination, phonological awareness, rapid automatized naming, fluency, and decoding. The at-risk intervention group showed improvement on the phoneme discrimination task after the intervention and outperformed the at-risk control group but not the typical control group. In addition, growth was observed during both the training and testing sessions of the intervention. The lexical specificity intervention could be a good resource to enhance a key precursor to literacy development for at-risk EBs.
Optimising rabies vaccination of dogs in India
Authors: Cuddington Kim , McAuliffe William H. B.
Published: August 2023

Dog vaccination is the key to controlling rabies in human populations. However, in countries like India, with large free-roaming dog populations, vaccination strategies that rely only on parenteral vaccines are unlikely to be either feasible or successful. Oral rabies vaccines could be used to reach these dogs. We use cost estimates for an Indian city and linear optimisation to find the most cost-effective vaccination strategies. We show that an oral bait handout method for dogs that are never confined can reduce the per dog costs of vaccination and increase vaccine coverage. This finding holds even when baits cost up to 10x the price of parenteral vaccines, if there is a large dog population or proportion of dogs that are never confined. We suggest that oral rabies vaccine baits will be part of the most cost-effective strategies to eliminate human deaths from dog-mediated rabies by 2030.
Culinary medicine and healthy ageing: a comprehensive review
Authors: Domper Jara , Gayoso Lucía , Goni Leticia , de la O Victor , Etxeberria Usune , Ruiz-Canela Miguel
Published: August 2023

Culinary medicine (CM) represents a novel strategy to promote healthy ageing, as it improves adherence to healthy dietary patterns by providing nutritional education and training in cooking skills. We conducted a comprehensive review of the current scientific literature (2011–2022) concerning CM programmes implemented among participants over the age of 40. This review includes fourteen culinary-nutritional interventions. Each CM programme was analysed according to seven variables: health goal, study design, theoretical basis of the intervention, intervention duration, main outcomes, culinary intervention and the effectiveness of intervention. Although CM programmes showed low effectiveness in achieving positive results on psychosocial outcomes, they were successful in improving dietary intake and health-related outcomes. The interventions lasting for at least 5 months and employing study designs with two or more groups seemed to be important factors associated with achieving significant results. Significant results were observed regardless of the prevention phase defined as the health objective of the CM programme. The use of theoretical frameworks as an educational resource did not influence the effectiveness of the interventions. Other variables such as the inclusion of culinary outcomes, the optimisation of the culinary curriculum taught to the participants and the participation of a chef in the intervention are factors that should be taken into account. In addition, several educational components (cooking classes, hands-on cooking, free food delivery, individualized counselling) were promising for achieving health outcomes in ageing people. Our review has shown that CM programmes can be a powerful tool to improve the health status of ageing people.
Why We Explain - Review of Anya Plutynski, 2018. Explaining Cancer: Finding Order in Disorder, Oxford University Press.
Authors: Ho Dien
Published: August 2023

Since its initial publication in 2018, Professor Anya Plutynski’s Explaining Cancer: Finding Order in Disorder has garnered a great deal of accolades.1 In 2021, The London School of Economics and Political Science conferred Professor Plutynski the Lakatos Award, recognizing the book’s significant contribution to the philosophy of science. On the heels of its recent reissuing as a paperback, it is an ideal time to revisit this remarkable work.
Strategic Ambiguity: The Pragmatic Utopianism of Daniel Callahan’s “Bioethics as a Discipline”
Authors: Schütz Mathias
Published: August 2023

This article highlights the continuing relevance of a classic bioethical text, “Bioethics as a Discipline,” published by the Hastings Center’s cofounder Daniel Callahan in 1973. Connecting the text’s programmatic recommendations with later reflections and interventions Callahan wrote about the development of bioethics illuminates how the vision Callahan established and the reality this vision helped create were interrelated—just not in the way Callahan had hoped for. Although this portrait relies on an individual perception of the development of bioethics, it might nevertheless, through its unique linkage of different bioethical temporalities, contribute to a broader reassessment of what bioethics became and why.
The Aesthetics of Musical Complex Systems
Authors: Sanfilippo Dario
Published: August 2023

This article introduces the history and aesthetics of feedback-based music, from early practitioners to more advanced methods and state-of-the-art works based on adaptation. Some of the most relevant techniques developed over almost six decades of investigations in the area of recursive systems for electronic music are discussed to show the variety and richness that a single specialised domain can have, providing examples of how scientific and philosophical principles can be translated into music. The historical context is key to understanding the evolution of the field: feedback-based music arose during the same years in which cybernetics, together with other disciplines, were experiencing a profound transformation. I will provide an overview of how such disciplines changed, highlighting the connections between seemingly distant areas such as philosophy, biology and engineering, and the fact that the development of feedback-based music appears to have followed somewhat closely the evolution of systems thinking. Finally, the article explores questions of musical aesthetics and music theory related to the use of complex autonomous systems in live performance through observations on the author’s creative practice.
Population genetic variation of microsatellite markers developed for Siberian fir (Abies sibirica Ledeb.) and European silver fir (Abies alba Mill.) using whole genome sequencing data
Authors: Oreshkova Natalia V. , Bondar Eugenia I. , Sharov Vadim V. , Dhungana Sudha P. , Gailing Oliver , Krutovsky Konstantin V.
Published: August 2023

The article presents the results of the search for microsatellite or simple sequence repeat (SSR) loci with tri-, tetra-, penta- and hexanucleotide tandem repeat motifs in the draft de novo assembly of the Siberian fir (Abies sibirica Ledeb.) genome and the development of convenient relatively highly and moderately polymorphic markers that can be easily genotyped even by simple gel electrophoresis. In total, 64 pairs of oligonucleotide polymerase chain reaction (PCR) primers for 32 detected microsatellite loci were designed and tested. Based on the testing results, 10 most promising polymorphic loci were selected and genotyped in eight natural populations of Siberian fir. Homologous microsatellite loci in the genome of European silver fir (Abies alba Mill.) were also identified by mapping Siberian fir contigs, containing SSR loci to the European silver fir genome assembly. A multiplex panel of 14 universal microsatellite loci was developed and genotyped in samples from four natural populations of A. alba and a small sample of eight Nordmann fir (Abies nordmanniana (Steven) Spach) trees.
Another brick in the wall: Climate change (in)adaptation under the law of belligerent occupation
Authors: Baudichau Eva
Published: August 2023

This article explores the legal obligations of Occupying Powers with regard to climate change adaptation for local populations and their environment under the law of occupation, specifically in the context of prolonged belligerent occupations. It focuses on the critical matter of water and food security, in light of the increasing frequency and severity of extreme weather events. After shedding light on the intricate issues that arise at the intersection of climate change and belligerent occupation, the article argues that the general obligations incumbent upon the Occupying Power under occupation law, when viewed through a climate lens, can be construed as addressing the heightened climate vulnerability faced by occupied populations.
PlanetProfile: Self‐Consistent Interior Structure Modeling for Ocean Worlds and Rocky Dwarf Planets in Python
Authors: Styczinski M. J. , Vance S. D. , Melwani Daswani M.
Published: August 2023

The open‐source PlanetProfile framework was developed to investigate the interior structure of icy moons based on collectively matching their observed properties and comparative planetology. The software relates observed and measured properties, assumptions such as the type of materials present, and laboratory equation‐of‐state (EOS) data through geophysical and thermodynamic models to evaluate radial profiles of mechanical, thermodynamic, and electrical properties, as self‐consistently as possible. We have created a Python version of PlanetProfile. In the process, we have made optimization improvements and added parallelization and parameter‐space search features to utilize fast operation for investigating unresolved questions in planetary geophysics, in which many model inputs are poorly constrained. The Python version links to other scientific software packages, including for evaluating EOS data, magnetic induction calculations, and seismic calculations. Physical models in PlanetProfile have been reconfigured to improve self‐consistency and generate the most realistic relationships between properties. In this work, we focus on the description of the software design and algorithms in detail, summarize model results for major moons across the outer solar system, and discuss new inferences about the interior structure of several bodies. The high values and narrow uncertainty ranges reported for the axial moments of inertia for Callisto, Titan, and Io are difficult to reconcile with the realistic physical and chemical approximations applied, requiring highly porous rock layers equivalent to incomplete differentiation for Callisto and Titan, and a high rock melt fraction for Io. Radial profiles for each model and comparison to prior work are provided as Zenodo archives.
Scenario Discovery Analysis of Drivers of Solar and Wind Energy Transitions Through 2050
Authors: Woodard Dawn L. , Snyder Abigail , Lamontagne Jonathan R. , Tebaldi Claudia , Morris Jennifer , Calvin Katherine V. , Binsted Matthew , Patel Pralit
Published: August 2023

Deep human‐Earth system uncertainties and strong multi‐sector dynamics make it difficult to anticipate which conditions are most likely to lead to higher or lower adoption of renewable energy, and models project a broad range of future solar and wind energy shares across future scenarios. To elucidate these dynamics, we explore a large data set of scenarios simulated from the Global Change Analysis Model (GCAM), and use scenario discovery to identify the most significant factors affecting solar and wind adoption by mid‐century. We generated a data set of over 4,000 scenarios from GCAM by varying 12 different socioeconomic factors at high and low levels, including assumptions about future energy demand, resource costs, and fossil fuel emissions paths, as well as specific technology assumptions including wind and solar backup requirements and storage costs. Using scenario discovery, we assess the most important factors globally and regionally in creating high fractions of solar and wind energy and explore interconnected effects on other systems including water and non‐CO2 emissions. Globally and regionally, we found that solar and wind‐related technology costs were the primary drivers of high wind and solar energy adoption, though a few regions depend heavily on other parameters like carbon capture and storage costs, population and gross domestic product trajectories, and fossil fuel costs. We also identify four key paths to high solar and wind energy by mid‐century and discuss their tradeoffs in terms of other outcomes.
Scaling the Bubble Penetration Depth in the Ocean
Authors: Cifuentes‐Lorenzen A. , Zappa C. J. , Randolph K. , Edson J. B.
Published: August 2023

Bubble plume penetration depths have been identified as a key parameter linking subsurface turbulent kinetic energy (TKE) dissipation rates and whitecaps. From data collected in the Atlantic sector of the Southern Ocean, nominally 50°S 40°W, bubble plume penetration depths were estimated from Acoustic Doppler Current Profiler measurements of the acoustic backscatter anomaly. Bubble presence at depth was corroborated using independent measurements of optical scattering. Here, an effective wavelength, observations of significant wave height and atmospheric forcing were used to scale penetration depths of breaking waves under open ocean conditions. The parameterization was developed assuming a correlation between the observed penetration depth and an estimate of the TKE dissipation rate enhancement under breaking waves. The effective wavelength was defined from the effective phase speed based on a momentum and energy balance across the atmospheric wave boundary layer and was considered to be the largest actively wind‐coupled wave and representative of large‐scale breaking for wave ages ranging from 15 to 35 (i.e., 15 ≤ 〈cp/u*〉 ≤ 35). This yields a dimensional penetration depth parameterization in terms of inverse wave age and the length scales under consideration. The parameterization captures the bubble plume penetration depth with stronger forcing leading to deeper injections, reaching up to 9 m. Both length scales are effective at defining the depth of a wave‐affected layer in terms of bubble presence with the effective wavelength better collapsing the data under mixed conditions with deeper plumes associated to larger fractional whitecap coverage.
Strain Threshold for the Formation of Coseismic Surface Rupture
Authors: Li Chenglong , Li Tao , Hollingsworth James , Zhang Yingfeng , Qian Li , Shan Xinjian
Published: August 2023

The 2021 Mw 7.4 Maduo earthquake (eastern Tibetan Plateau), with a surface deformation zone that is characterized by multiple distinct surface rupture segments separated by segments with no surface ruptures, provides an excellent opportunity to constrain the strain threshold (minimum strain) for the formation of surface ruptures. Through sub‐pixel correlation of pre‐ and post‐event SPOT‐6/7 satellite images (pixel = 1.5 m), we derive surface displacement and shear‐strain fields of the Maduo earthquake. By quantifying the minimum shear strain along the surface rupture segments and the maximum shear strain along the segments with no surface ruptures, we estimate a rupture strain threshold, which ranges from 0.8% to 1.8% and appears to decrease with structural maturity of the causative fault. This threshold is generally consistent with a rupture strain limit (0.5%–1.5%) of intact rocks from laboratory measurements, and is higher than a commonly‐assumed strain threshold (0.5%) for inelastic deformation.
Dynamic Fluid Connectivity Controls Solute Dispersion in Multiphase Porous Media Flow
Authors: Mathiesen Joachim , Linga Gaute , Misztal Marek , Renard François , Le Borgne Tanguy
Published: August 2023

Solute transport in multiphase flow through porous media plays a central role in many natural systems and geoengineering applications. The interplay between fluid flow and capillary forces leads to transient flow dynamics and phase distributions. However, it is not known how such dynamic flow affects the dispersion of transported species. Here, we use highly resolved numerical simulations of immiscible two‐phase flow to investigate dispersion in multiphase flows. We show that repeated activation and deactivation of different flow pathways under the effect of capillary forces accelerates the spreading of solutes compared to single phase flow. We establish the transport laws under dynamic multiphase flows by linking the dispersion coefficient to the Bond number, the ratio of the force driving the flow and the surface tension. Our results determine the controlling factors for solute dispersion in porous media, opening a range of applications for understanding and controlling transport in porous geological systems.
Focal Mechanism Determination of Event S1222a and Implications for Tectonics Near the Dichotomy Boundary in Southern Elysium Planitia, Mars
Authors: Maguire R. , Lekić V. , Kim D. , Schmerr N. , Li J. , Beghein C. , Huang Q. , Irving J. C. E. , Karakostas F. , Lognonné P. , Stähler S. C. , Banerdt W. B.
Published: August 2023

On 4 May 2022 the InSight seismometer SEIS‐VBB recorded the largest marsquake ever observed, S1222a, with an initial magnitude estimate of 4.6. Understanding the depth and source properties of this event has important implications for the nature of tectonic activity on Mars. Located ∼37° to the southeast of InSight, S1222a is one of the few non‐impact marsquakes that exhibits prominent surface waves. We use waveform modeling of body waves (P and S) and surface waves (Rayleigh and Love) to constrain the focal mechanism, assuming a double‐couple source, and find that S1222a likely resulted from reverse faulting in the crust (source depth near 22 km). We estimate the scalar moment to be 2.5 × 1015–3.5 × 1015 Nm (magnitude MW 4.2–4.3). Our results suggest active compressional tectonics near the dichotomy boundary on Mars, likely due to thermal contraction from planetary cooling.
Sea‐Level Rise Impacts on Tidal Marshes and Estuarine Biogeochemical Processes
Authors: Cai Xun , Shen Jian , Zhang Yinglong J. , Qin Qubin , Linker Lewis
Published: August 2023

We used a numerical model to investigate the effects of sea‐level rise (SLR) on the biogeochemical processes in the York River Estuary with extensive tidal marshes. The fully‐coupled hydrodynamic‐water quality‐marsh model accounts for the spatial and temporal variations of physical‐biogeochemical interactions between the tidal marshes and surrounding waters. This study focuses on an SLR scenario where the vertical accretion of tidal marshes keeps pace with the rising sea levels. Results show that SLR amplifies the tidal range and prolongs flooding duration, which results in enhanced porewater exchanges of materials between the tidal marshes and the surrounding waters. The increased availability of shallow‐water habitats and enhanced light utilization in the shallow areas under SLR promote phytoplankton production (PP) in the shallow‐water regions of the York River. Consequently, the organic carbon in the open water is fueled by the contributions from shallow waters and the enhanced export of organic carbon from the marshes. The change in the dissolved oxygen (DO) budget in the York River Estuary is attributed to changes in water column respiration, net metabolism of the benthic layer, reaeration, PP, and increased stratification under SLR. The net DO flux out of the York River increases at the York River mouth. Diel DO variation, especially in the marshes in the upper estuary, promotes phosphorus release from the sediment. The changes in dissolved nitrogen under SLR are relatively minimal.
α-parvin controls chondrocyte column formation and regulates long bone development
Authors: Yuan Jifan , Guo Ling , Wang Jiaxin , Zhou Zhongjun , Wu Chuanyue
Published: August 2023

Endochondral ossification requires proper control of chondrocyte proliferation, differentiation, survival, and organization. Here we show that knockout of α-parvin, an integrin-associated focal adhesion protein, from murine limbs causes defects in endochondral ossification and dwarfism. The mutant long bones were shorter but wider, and the growth plates became disorganized, especially in the proliferative zone. With two-photon time-lapse imaging of bone explant culture, we provide direct evidence showing that α-parvin regulates chondrocyte rotation, a process essential for chondrocytes to form columnar structure. Furthermore, loss of α-parvin increased binucleation, elevated cell death, and caused dilation of the resting zones of mature growth plates. Single-cell RNA-seq analyses revealed alterations of transcriptome in all three zones (i.e., resting, proliferative, and hypertrophic zones) of the growth plates. Our results demonstrate a crucial role of α-parvin in long bone development and shed light on the cellular mechanism through which α-parvin regulates the longitudinal growth of long bones.
Cancer-associated fibroblasts: tumor defenders in radiation therapy
Authors: Zhang Yalin , Lv Na , Li Manshi , Liu Ming , Wu Chunli
Published: August 2023

Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment that are involved in multiple aspects of cancer progression and considered contributors to tumor immune escape. CAFs exhibit a unique radiation resistance phenotype, and can survive clinical radiation doses; however, ionizing radiation can induce changes in their secretions and influence tumor progression by acting on tumor and immune cells. In this review, we describe current knowledge of the effects of radiation therapies on CAFs, as well as summarizing understanding of crosstalk among CAFs, tumor cells, and immune cells. We highlight the important role of CAFs in radiotherapy resistance, and discuss current and future radiotherapy strategies for targeting CAFs.
The deubiquitinase Leon/USP5 interacts with Atg1/ULK1 and antagonizes autophagy
Authors: Pai Yueh-Ling , Lin Yuchieh Jay , Peng Wen-Hsin , Huang Li-Ting , Chou He-Yen , Wang Chien-Hsiang , Chien Cheng-Ting , Chen Guang-Chao
Published: August 2023

Accumulating evidence has shown that the quality of proteins must be tightly monitored and controlled to maintain cellular proteostasis. Misfolded proteins and protein aggregates are targeted for degradation through the ubiquitin proteasome (UPS) and autophagy-lysosome systems. The ubiquitination and deubiquitinating enzymes (DUBs) have been reported to play pivotal roles in the regulation of the UPS system. However, the function of DUBs in the regulation of autophagy remain to be elucidated. In this study, we found that knockdown of Leon/USP5 caused a marked increase in the formation of autophagosomes and autophagic flux under well-fed conditions. Genetic analysis revealed that overexpression of Leon suppressed Atg1-induced cell death inDrosophila. Immunoblotting assays further showed a strong interaction between Leon/USP5 and the autophagy initiating kinase Atg1/ULK1. Depletion of Leon/USP5 led to increased levels of Atg1/ULK1. Our findings indicate that Leon/USP5 is an autophagic DUB that interacts with Atg1/ULK1, negatively regulating the autophagic process.
Storylines for unprecedented heatwaves based on ensemble boosting
Authors: Fischer E. M. , Beyerle U. , Bloin-Wibe L. , Gessner C. , Humphrey V. , Lehner F. , Pendergrass A. G. , Sippel S. , Zeder J. , Knutti R.
Published: August 2023

Recent temperature extremes have shattered previously observed records, reaching intensities that were inconceivable before the events. Could the possibility of an event with such unprecedented intensity as the 2021 Pacific Northwest heatwave have been foreseen, based on climate model information available before the event? Could the scientific community have quantified its potential intensity based on the current generation of climate models? Here, we demonstrate how an ensemble boosting approach can be used to generate physically plausible storylines of a heatwave hotter than observed in the Pacific Northwest. We also show that heatwaves of much greater intensities than ever observed are possible in other locations like the Greater Chicago and Paris regions. In order to establish confidence in storylines of ‘black swan’-type events, different lines of evidence need to be combined along with process understanding to make this information robust and actionable for stakeholders.
Bat teeth illuminate the diversification of mammalian tooth classes
Authors: Sadier Alexa , Anthwal Neal , Krause Andrew L. , Dessalles Renaud , Lake Michael , Bentolila Laurent A. , Haase Robert , Nieves Natalie A. , Santana Sharlene E. , Sears Karen E.
Published: August 2023

Tooth classes are an innovation that has contributed to the evolutionary success of mammals. However, our understanding of the mechanisms by which tooth classes diversified remain limited. We use the evolutionary radiation of noctilionoid bats to show how the tooth developmental program evolved during the adaptation to new diet types. Combining morphological, developmental and mathematical modeling approaches, we demonstrate that tooth classes develop through independent developmental cascades that deviate from classical models. We show that the diversification of tooth number and size is driven by jaw growth rate modulation, explaining the rapid gain/loss of teeth in this clade. Finally, we mathematically model the successive appearance of tooth buds, supporting the hypothesis that growth acts as a key driver of the evolution of tooth number and size. Our work reveal how growth, by tinkering with reaction/diffusion processes, drives the diversification of tooth classes and other repeated structure during adaptive radiations.
TUG1-mediated R-loop resolution at microsatellite loci as a prerequisite for cancer cell proliferation
Authors: Suzuki Miho M. , Iijima Kenta , Ogami Koichi , Shinjo Keiko , Murofushi Yoshiteru , Xie Jingqi , Wang Xuebing , Kitano Yotaro , Mamiya Akira , Kibe Yuji , Nishimura Tatsunori , Ohka Fumiharu , Saito Ryuta , Sato Shinya , Kobayashi Junya , Yao Ryoji , Miyata Kanjiro , Kataoka Kazunori , Suzuki Hiroshi I. , Kondo Yutaka
Published: August 2023

Oncogene-induced DNA replication stress (RS) and consequent pathogenic R-loop formation are known to impede S phase progression. Nonetheless, cancer cells continuously proliferate under such high-stressed conditions through incompletely understood mechanisms. Here, we report taurine upregulated gene 1 (TUG1) long noncoding RNA (lncRNA), which is highly expressed in many types of cancers, as an important regulator of intrinsic R-loop in cancer cells. Under RS conditions, TUG1 is rapidly upregulated via activation of the ATR-CHK1 signaling pathway, interacts with RPA and DHX9, and engages in resolving R-loops at certain loci, particularly at the CA repeat microsatellite loci. Depletion of TUG1 leads to overabundant R-loops and enhanced RS, leading to substantial inhibition of tumor growth. Our data reveal a role of TUG1 as molecule important for resolving R-loop accumulation in cancer cells and suggest targeting TUG1 as a potent therapeutic approach for cancer treatment.
Impaired Plakophilin-2 in obesity breaks cell cycle dynamics to breed adipocyte senescence
Authors: Lluch Aina , Latorre Jessica , Serena-Maione Angela , Espadas Isabel , Caballano-Infantes Estefanía , Moreno-Navarrete José M. , Oliveras-Cañellas Núria , Ricart Wifredo , Malagón María M. , Martin-Montalvo Alejandro , Birchmeier Walter , Szymanski Witold , Graumann Johannes , Gómez-Serrano María , Sommariva Elena , Fernández-Real José M. , Ortega Francisco J.
Published: August 2023

Plakophilin-2 (PKP2) is a key component of desmosomes, which, when defective, is known to promote the fibro-fatty infiltration of heart muscle. Less attention has been given to its role in adipose tissue. We report here that levels of PKP2 steadily increase during fat cell differentiation, and are compromised if adipocytes are exposed to a pro-inflammatory milieu. Accordingly, expression of PKP2 in subcutaneous adipose tissue diminishes in patients with obesity, and normalizes upon mild-to-intense weight loss. We further show defective PKP2 in adipocytes to break cell cycle dynamics and yield premature senescence, a key rheostat for stress-induced adipose tissue dysfunction. Conversely, restoring PKP2 in inflamed adipocytes rewires E2F signaling towards the re-activation of cell cycle and decreased senescence. Our findings connect the expression of PKP2 in fat cells to the physiopathology of obesity, as well as uncover a previously unknown defect in cell cycle and adipocyte senescence due to impaired PKP2.
Demethylase-independent roles of LSD1 in regulating enhancers and cell fate transition
Authors: Zeng Cheng , Chen Jiwei , Cooke Emmalee W. , Subuddhi Arijita , Roodman Eliana T. , Chen Fei Xavier , Cao Kaixiang
Published: August 2023

The major enhancer regulator lysine-specific histone demethylase 1A (LSD1) is required for mammalian embryogenesis and is implicated in human congenital diseases and multiple types of cancer; however, the underlying mechanisms remain enigmatic. Here, we dissect the role of LSD1 and its demethylase activity in gene regulation and cell fate transition. Surprisingly, the catalytic inactivation of LSD1 has a mild impact on gene expression and cellular differentiation whereas the loss of LSD1 protein de-represses enhancers globally and impairs cell fate transition. LSD1 deletion increases H3K27ac levels and P300 occupancy at LSD1-targeted enhancers. The gain of H3K27ac catalyzed by P300/CBP, not the loss of CoREST complex components from chromatin, contributes to the transcription de-repression of LSD1 targets and differentiation defects caused by LSD1 loss. Together, our study demonstrates a demethylase-independent role of LSD1 in regulating enhancers and cell fate transition, providing insight into treating diseases driven by LSD1 mutations and misregulation.
Longitudinal high-dimensional analysis identifies immune features associating with response to anti-PD-1 immunotherapy
Authors: Leung Elaine Lai-Han , Li Run-Ze , Fan Xing-Xing , Wang Lily Yan , Wang Yan , Jiang Zebo , Huang Jumin , Pan Hu-Dan , Fan Yue , Xu Hongmei , Wang Feng , Rui Haopeng , Wong Piu , Sumatoh Hermi , Fehlings Michael , Nardin Alessandra , Gavine Paul , Zhou Longen , Cao Yabing , Liu Liang
Published: August 2023

Response to immunotherapy widely varies among cancer patients and identification of parameters associating with favourable outcome is of great interest. Here we show longitudinal monitoring of peripheral blood samples of non-small cell lung cancer (NSCLC) patients undergoing anti-PD1 therapy by high-dimensional cytometry by time of flight (CyTOF) and Meso Scale Discovery (MSD) multi-cytokines measurements. We find that higher proportions of circulating CD8+ and of CD8+CD101hiTIM3+ (CCT T) subsets significantly correlate with poor clinical response to immune therapy. Consistently, CD8+ T cells and CCT T cell frequencies remain low in most responders during the entire multi-cycle treatment regimen; and higher killer cell lectin-like receptor subfamily G, member 1 (KLRG1) expression in CCT T cells at baseline associates with prolonged progression free survival. Upon in vitro stimulation, CCT T cells of responders produce significantly higher levels of cytokines, including IL-1β, IL-2, IL-8, IL-22 and MCP-1, than of non-responders. Overall, our results provide insights into the longitudinal immunological landscape underpinning favourable response to immune checkpoint blockade therapy in lung cancer patients.
Direction-dependent dynamics of colloidal particle pairs and the Stokes-Einstein relation in quasi-two-dimensional fluids
Authors: Barbhuiya Noman Hanif , Yodh A. G. , Mishra Chandan K.
Published: August 2023

Hydrodynamic interactions are important for diverse fluids, especially those with low Reynolds number such as microbial and particle-laden suspensions, and proteins diffusing in membranes. Unfortunately, while far-field (asymptotic) hydrodynamic interactions are fully understood in two- and three-dimensions, near-field interactions are not, and thus our understanding of motions in dense fluid suspensions is still lacking. In this contribution, we experimentally explore the hydrodynamic correlations between particles in quasi-two-dimensional colloidal fluids in the near-field. Surprisingly, the measured displacement and relaxation of particle pairs in the body frame exhibit direction-dependent dynamics that can be connected quantitatively to the measured near-field hydrodynamic interactions. These findings, in turn, suggest a mechanism for how and when hydrodynamics can lead to a breakdown of the ubiquitous Stokes-Einstein relation (SER). We observe this breakdown, and we show that the direction-dependent breakdown of the SER is ameliorated along directions where hydrodynamic correlations are smallest. In total, the work uncovers significant ramifications of near-field hydrodynamics on transport and dynamic restructuring of fluids in two-dimensions.
A ferroptosis-targeting ceria anchored halloysite as orally drug delivery system for radiation colitis therapy
Authors: Feng Yue , Luo Xiang , Li Zichun , Fan Xinjuan , Wang Yiting , He Rong-Rong , Liu Mingxian
Published: August 2023

Radiation colitis is the leading cause of diarrhea and hematochezia in pelvic radiotherapy patients. This work advances the pathogenesis of radiation colitis from the perspective of ferroptosis. An oral Pickering emulsion is stabilized with halloysite clay nanotubes to alleviate radiation colitis by inhibiting ferroptosis. Ceria nanozyme grown in situ on nanotubes can scavenge reactive oxygen species, and deferiprone was loaded into the lumen of nanotubes to relieve iron stress. These two strategies effectively inhibit lipid peroxidation and rescue ferroptosis in the intestinal microenvironment. The clay nanotubes play a critical role as either a medicine to alleviate colitis, a nanocarrier that targets the inflamed colon by electrostatic adsorption, or an interfacial stabilizer for emulsions. This ferroptosis-based strategy was effective in vitro and in vivo, providing a prospective candidate for radiotherapy protection via rational regulation of specific oxidative stress.
Structural insights into opposing actions of neurosteroids on GABAA receptors
Authors: Legesse Dagimhiwat H. , Fan Chen , Teng Jinfeng , Zhuang Yuxuan , Howard Rebecca J. , Noviello Colleen M. , Lindahl Erik , Hibbs Ryan E.
Published: August 2023

γ-Aminobutyric acid type A (GABAA) receptors mediate fast inhibitory signaling in the brain and are targets of numerous drugs and endogenous neurosteroids. A subset of neurosteroids are GABAA receptor positive allosteric modulators; one of these, allopregnanolone, is the only drug approved specifically for treating postpartum depression. There is a consensus emerging from structural, physiological and photolabeling studies as to where positive modulators bind, but how they potentiate GABA activation remains unclear. Other neurosteroids are negative modulators of GABAA receptors, but their binding sites remain debated. Here we present structures of a synaptic GABAA receptor bound to allopregnanolone and two inhibitory sulfated neurosteroids. Allopregnanolone binds at the receptor-bilayer interface, in the consensus potentiator site. In contrast, inhibitory neurosteroids bind in the pore. MD simulations and electrophysiology support a mechanism by which allopregnanolone potentiates channel activity and suggest the dominant mechanism for sulfated neurosteroid inhibition is through pore block.
Acidification suppresses the natural capacity of soil microbiome to fight pathogenic Fusarium infections
Authors: Li Xiaogang , Chen Dele , Carrión Víctor J. , Revillini Daniel , Yin Shan , Dong Yuanhua , Zhang Taolin , Wang Xingxiang , Delgado-Baquerizo Manuel
Published: August 2023

Soil-borne pathogens pose a major threat to food production worldwide, particularly under global change and with growing populations. Yet, we still know very little about how the soil microbiome regulates the abundance of soil pathogens and their impact on plant health. Here we combined field surveys with experiments to investigate the relationships of soil properties and the structure and function of the soil microbiome with contrasting plant health outcomes. We find that soil acidification largely impacts bacterial communities and reduces the capacity of soils to combat fungal pathogens. In vitro assays with microbiomes from acidified soils further highlight a declined ability to suppress Fusarium, a globally important plant pathogen. Similarly, when we inoculate healthy plants with an acidified soil microbiome, we show a greatly reduced capacity to prevent pathogen invasion. Finally, metagenome sequencing of the soil microbiome and untargeted metabolomics reveals a down regulation of genes associated with the synthesis of sulfur compounds and reduction of key traits related to sulfur metabolism in acidic soils. Our findings suggest that changes in the soil microbiome and disruption of specific microbial processes induced by soil acidification can play a critical role for plant health.
Topological soliton molecule in quasi 1D charge density wave
Authors: Im Taehwan , Song Sun Kyu , Park Jae Whan , Yeom Han Woong
Published: August 2023

Soliton molecules, bound states of two solitons, can be important for the informatics using solitons and the quest for exotic particles in a wide range of physical systems from unconventional superconductors to nuclear matter and Higgs field, but have been observed only in temporal dimension for classical wave optical systems. Here, we identify a topological soliton molecule formed spatially in an electronic system, a quasi 1D charge density wave of indium atomic wires. This system is composed of two coupled Peierls chains, which are endowed with a Z4 topology and three distinct, right-chiral, left-chiral, and non-chiral, solitons. Our scanning tunneling microscopy measurements identify a bound state of right- and left-chiral solitons with distinct in-gap states and net zero phase shift. Our density functional theory calculations reveal the attractive interaction of these solitons and the hybridization of their electronic states. This result initiates the study of the interaction between solitons in electronic systems, which can provide novel manybody electronic states and extra data-handling capacity beyond the given soliton topology.
Novel insights into the role of long non-coding RNA in the human malaria parasite, Plasmodium falciparum
Authors: Batugedara Gayani , Lu Xueqing M. , Hristov Borislav , Abel Steven , Chahine Zeinab , Hollin Thomas , Williams Desiree , Wang Tina , Cort Anthony , Lenz Todd , Thompson Trevor A. , Prudhomme Jacques , Tripathi Abhai K. , Xu Guoyue , Cudini Juliana , Dogga Sunil , Lawniczak Mara , Noble William Stafford , Sinnis Photini , Le Roch Karine G.
Published: August 2023

The complex life cycle of Plasmodium falciparum requires coordinated gene expression regulation to allow host cell invasion, transmission, and immune evasion. Increasing evidence now suggests a major role for epigenetic mechanisms in gene expression in the parasite. In eukaryotes, many lncRNAs have been identified to be pivotal regulators of genome structure and gene expression. To investigate the regulatory roles of lncRNAs in P. falciparum we explore the intergenic lncRNA distribution in nuclear and cytoplasmic subcellular locations. Using nascent RNA expression profiles, we identify a total of 1768 lncRNAs, of which 718 (~41%) are novels in P. falciparum. The subcellular localization and stage-specific expression of several putative lncRNAs are validated using RNA-FISH. Additionally, the genome-wide occupancy of several candidate nuclear lncRNAs is explored using ChIRP. The results reveal that lncRNA occupancy sites are focal and sequence-specific with a particular enrichment for several parasite-specific gene families, including those involved in pathogenesis and sexual differentiation. Genomic and phenotypic analysis of one specific lncRNA demonstrate its importance in sexual differentiation and reproduction. Our findings bring a new level of insight into the role of lncRNAs in pathogenicity, gene regulation and sexual differentiation, opening new avenues for targeted therapeutic strategies against the deadly malaria parasite.
Convergent somatic evolution commences in utero in a germline ribosomopathy
Authors: Machado Heather E. , Øbro Nina F. , Williams Nicholas , Tan Shengjiang , Boukerrou Ahmed Z. , Davies Megan , Belmonte Miriam , Mitchell Emily , Baxter E. Joanna , Mende Nicole , Clay Anna , Ancliff Philip , Köglmeier Jutta , Killick Sally B. , Kulasekararaj Austin , Meyer Stefan , Laurenti Elisa , Campbell Peter J. , Kent David G. , Nangalia Jyoti , Warren Alan J.
Published: August 2023

Clonal tracking of cells using somatic mutations permits exploration of clonal dynamics in human disease. Here, we perform whole genome sequencing of 323 haematopoietic colonies from 10 individuals with the inherited ribosomopathy Shwachman-Diamond syndrome to reconstruct haematopoietic phylogenies. In ~30% of colonies, we identify mutually exclusive mutations in TP53, EIF6, RPL5, RPL22, PRPF8, plus chromosome 7 and 15 aberrations that increase SBDS and EFL1 gene dosage, respectively. Target gene mutations commence in utero, resulting in a profusion of clonal expansions, with only a few haematopoietic stem cell lineages (mean 8, range 1-24) contributing ~50% of haematopoietic colonies across 8 individuals (range 4-100% clonality) by young adulthood. Rapid clonal expansion during disease transformation is associated with biallelic TP53 mutations and increased mutation burden. Our study highlights how convergent somatic mutation of the p53-dependent nucleolar surveillance pathway offsets the deleterious effects of germline ribosomopathy but increases opportunity for TP53-mutated cancer evolution.
Revealing the secrets of a 2900-year-old clay brick, discovering a time capsule of ancient DNA
Authors: Arbøll Troels Pank , Rasmussen Sophie Lund , de Jonge Nadieh , Hansen Anne Haslund , Pertoldi Cino , Nielsen Jeppe Lund
Published: August 2023

The recent development of techniques to sequence ancient DNA has provided valuable insights into the civilisations that came before us. However, the full potential of these methods has yet to be realised. We extracted ancient DNA from a recently exposed fracture surface of a clay brick deriving from the palace of king Ashurnasirpal II (883–859 BCE) in Nimrud, Iraq. We detected 34 unique taxonomic groups of plants. With this research we have made the pioneering discovery that ancient DNA, effectively protected from contamination inside a mass of clay, can successfully be extracted from a 2900-year-old clay brick. We encourage future research into this subject, as the scientific prospects for this approach are substantial, potentially leading to a deeper understanding of ancient and lost civilisations.
Relationship chains of subhealth physical examination indicators: a cross-sectional study using the PLS-SEM approach
Authors: Wang Yu , Lou Jindi , Li Jun , Shi Yulin , Jiang Tao , Tu Liping , Xu Jiatuo
Published: August 2023

Subhealth is a transitional state between health and disease, and it can be detected through routine physical check-ups. However, the complexity and diversity of physical examination items and the difficulty of quantifying subhealth manifestations are the main problems that hinder its treatment. The aim of this study was to systematically investigate the physical examination performance of the subhealthy population and further explore the deeper relationships between indicators. Indicators were obtained for 878 subjects, including basic information, Western medicine indicators, inquiries of traditional Chinese medicine and sublingual vein (SV) characteristics. Statistical differences were analysed using R software. To explore the distribution of symptoms and symptom clusters in subhealth, partial least squares-structural equation modelling (PLS-SEM) was applied to the subhealth physical examination index, and a structural model was developed to verify whether the relationship chain between the latent variables was reasonable. Finally, the reliability and validity of the PLS-SE model were assessed. The most common subclinical clinical symptoms were limb soreness (37.6%), fatigue (31.6%), shoulder and neck pain (30.5%) and dry eyes (29.2%). The redness of the SV in the subhealthy group was paler than that in the healthy group (p < 0.001). This study validates the establishment of the directed acyclic relationship chain in the subhealthy group: the path from routine blood tests to lipid metabolism (t = 7.878, p < 0.001), the path from lipid metabolism to obesity (t = 8.410, p < 0.001), the path from obesity to SV characteristics (t = 2.237, p = 0.025), and the path from liver function to SV characteristics (t = 2.215, p = 0.027). The innovative application of PLS-SEM to the study of subhealth has revealed the existence of a chain of relationships between physical examination indicators, which will provide a basis for further exploration of subhealth mechanisms and causal inference. This study has identified the typical symptoms of subhealth, and their early management will help to advance the treatment of diseases.