bluuebunny/crossref_metadata_2025_split huggingface dataset:
Strongly Versus Weakly Coupled Data Assimilation in Coupled Systems With Various Inter‐Compartment Interactions
Authors: Miwa Norihiro , Sawada Yohei 
Published: February 2024

AbstractCoupled data assimilation (CDA) has been attracting researchers' interests to improve Earth system modeling. The CDA methods are classified into two: weakly coupled data assimilation (wCDA), which considers cross‐compartment interaction only in a forecast phase, and strongly coupled data assimilation (sCDA), which additionally uses other compartment's information in an analysis phase. Although sCDA can theoretically provide better estimates than wCDA since sCDA fully uses inter‐compartment covariances, the potential of sCDA in practice is still in debate. We investigate conditions under which sCDA is effective by applying Local Ensemble Transform Kalman Filter (LETKF) to a coupled Lorenz96 model. Especially, we aim to generalize CDA's behavior on coupling strength basis. By continuously changing a cross‐compartment interaction in the coupled Lorenz96 model, we find that sCDA's superiority over wCDA is particularly evident with large cross‐compartment interactions which attenuates dynamics of each compartment (the increase of variables in one compartment induces the reduction of those in the other compartment) and does not intensify the chaoticity of the whole system. The performance of sCDA is more sensitive to the LETKF's hyperparameters (i.e., localization and inflation) than wCDA. Furthermore, through two imperfect model experiments in which model parameters are uncertain, we quantify sCDA's vulnerability to model inaccuracies. The findings of the relationship between the skill of sCDA and inter‐compartment interactions give implications for future CDA strategies.
Glacier Melting Triggers Massive Gravel Deposition in Central Italy's River Basins, Unveiling Deglacial Events From 1250 to 780 ka
Authors: Florindo F. , Marra F. , Jicha B. R. , Bulian F. , Di Chiara A. , Srivastava P. 
Published: February 2024

AbstractThe purpose of this study was to prove the direct correlation of a successions of gravel‐clay beds recovered in borehole with the melt‐water pulses associated with the sea‐level oscillations indicated in the δ18O record in the time‐span preceding the 100‐kyr glacial cycles. Aimed at this scope, we provide combined 40Ar/39Ar and paleomagnetic constraints to a set of seven aggradational successions recovered from a 120 m deep borehole drilled in the buried Paleo‐Tiber delta in Rome (central Italy). The geochronologic constraints enable the correlation of each aggradational succession, characterized by a sudden transition from coarse gravel at the base to sandy clay sediments, with periods of sea‐level rise indicated by the δ18O curve encompassing MIS 37 through MIS 19, from 1250 to 780 ka. This stratigraphy, provides a unique and unprecedented well‐dated evidence of glacial/deglacial events, matching the global benthic δ18O stack during this time frame. Furthermore, this study validates the hypothesis that gravel deposition in the catchment basin and the delta of the main rivers in central Italy is triggered by the melting of glaciers in the Apennines Mountain range. It demonstrates the significant potential of these deglaciation proxies to be used worldwide to unravel the chronology of glacio‐eustatic events.
The osteoclastic activity in apical distal region of molar mesial roots affects orthodontic tooth movement and root resorption in rats
Authors: Zheng Wenhao , Lu Xiaofeng , Chen Guangjin , Shen Yufeng , Huang Xiaofei , Peng Jinfeng , Wang Jiajia , Yin Ying , Song Wencheng , Xie Mengru , Yu Shaoling , Chen Lili 
Published: February 2024

AbstractThe utilization of optimal orthodontic force is crucial to prevent undesirable side effects and ensure efficient tooth movement during orthodontic treatment. However, the sensitivity of existing detection techniques is not sufficient, and the criteria for evaluating optimal force have not been yet established. Here, by employing 3D finite element analysis methodology, we found that the apical distal region (A-D region) of mesial roots is particularly sensitive to orthodontic force in rats. Tartrate-resistant acidic phosphatase (TRAP)-positive osteoclasts began accumulating in the A-D region under the force of 40 grams (g), leading to alveolar bone resorption and tooth movement. When the force reached 80 g, TRAP-positive osteoclasts started appearing on the root surface in the A-D region. Additionally, micro-computed tomography revealed a significant root resorption at 80 g. Notably, the A-D region was identified as a major contributor to whole root resorption. It was determined that 40 g is the minimum effective force for tooth movement with minimal side effects according to the analysis of tooth movement, inclination, and hyalinization. These findings suggest that the A-D region with its changes on the root surface is an important consideration and sensitive indicator when evaluating orthodontic forces for a rat model. Collectively, our investigations into this region would aid in offering valuable implications for preventing and minimizing root resorption during patients’ orthodontic treatment.
GRID1/GluD1 homozygous variants linked to intellectual disability and spastic paraplegia impair mGlu1/5 receptor signaling and excitatory synapses
Authors: Ung Dévina C. , Pietrancosta Nicolas , Badillo Elena Baz , Raux Brigitt , Tapken Daniel , Zlatanovic Andjela , Doridant Adrien , Pode-Shakked Ben , Raas-Rothschild Annick , Elpeleg Orly , Abu-Libdeh Bassam , Hamed Nasrin , Papon Marie-Amélie , Marouillat Sylviane , Thépault Rose-Anne , Stevanin Giovanni , Elegheert Jonathan , Letellier Mathieu , Hollmann Michael , Lambolez Bertrand , Tricoire Ludovic , Toutain Annick , Hepp Régine , Laumonnier Frédéric 
Published: February 2024

AbstractThe ionotropic glutamate delta receptor GluD1, encoded by the GRID1 gene, is involved in synapse formation, function, and plasticity. GluD1 does not bind glutamate, but instead cerebellin and D-serine, which allow the formation of trans-synaptic bridges, and trigger transmembrane signaling. Despite wide expression in the nervous system, pathogenic GRID1 variants have not been characterized in humans so far. We report homozygous missense GRID1 variants in five individuals from two unrelated consanguineous families presenting with intellectual disability and spastic paraplegia, without (p.Thr752Met) or with (p.Arg161His) diagnosis of glaucoma, a threefold phenotypic association whose genetic bases had not been elucidated previously. Molecular modeling and electrophysiological recordings indicated that Arg161His and Thr752Met mutations alter the hinge between GluD1 cerebellin and D-serine binding domains and the function of this latter domain, respectively. Expression, trafficking, physical interaction with metabotropic glutamate receptor mGlu1, and cerebellin binding of GluD1 mutants were not conspicuously altered. Conversely, upon expression in neurons of dissociated or organotypic slice cultures, we found that both GluD1 mutants hampered metabotropic glutamate receptor mGlu1/5 signaling via Ca2+ and the ERK pathway and impaired dendrite morphology and excitatory synapse density. These results show that the clinical phenotypes are distinct entities segregating in the families as an autosomal recessive trait, and caused by pathophysiological effects of GluD1 mutants involving metabotropic glutamate receptor signaling and neuronal connectivity. Our findings unravel the importance of GluD1 receptor signaling in sensory, cognitive and motor functions of the human nervous system.
Lipoprotein(a) serum concentrations in children in relation to body mass index, age and sex
Authors: Stürzebecher Paulina E. , Uttinger Konstantin L. , Vogel Mandy , Schlingmann Maike , Ceglarek Uta , Isermann Berend , Kiess Wieland , Körner Antje , Laufs Ulrich 
Published: February 2024

Abstract
Background
Lipoprotein(a) (Lp(a)) is an inherited risk factor for atherosclerotic cardiovascular disease (ASCVD). Limited data exist on Lp(a) values in children. We aimed to evaluate whether Lp(a) concentrations in youth are influenced by BMI.

Methods
756 blood samples of 248 children with obesity and 264 matched healthy children aged 5 and 18 years, enrolled in the population-based LIFE Child (German civilization diseases cohort) study, were analyzed. Repeat measurements were available in 154 children (1–4 follow ups, ~1 year apart).

Results
The median Lp(a) concentration in the total cohort (n = 512) at first visit was 9.7 mg/dL (IQR 4.0–28.3). Lp(a) concentrations between 30–50 mg/dL were observed in 11.5%, while 12.5% exhibited Lp(a) ≧50 mg/dL. There was no association of Lp(a) with body mass index (BMI) (ß = 0.004, P = 0.49). Lp(a) levels did not correlate with age or sex, while Lp(a) was associated positively with low-density lipoprotein cholesterol (ß = 0.05, P < 0.0001). The Lp(a) risk category remained stable in 94% of all children in repeated measurements.

Conclusions
The data showed no association of Lp(a) levels in children with BMI, age or sex. Measurement of Lp(a) in youth may be useful to identify children at increased lifetime risk for ASCVD.

Impact

In youth, Lp(a) levels are not affected by age, sex and BMI.

Lp(a) risk categories remain stable over time in repeated measurements in children.

Measurement of Lp(a) in children may be useful as an additional factor to identify children at increased lifetime risk for ASCVD and for reverse family screening.
mTOR pathway occupies a central role in the emergence of latent cancer cells
Authors: Aleksandrova Kseniia V. , Vorobev Mikhail L. , Suvorova Irina I. 
Published: February 2024

AbstractThe current focus in oncology research is the translational control of cancer cells as a major mechanism of cellular plasticity. Recent evidence has prompted a reevaluation of the role of the mTOR pathway in cancer development leading to new conclusions. The mechanistic mTOR inhibition is well known to be a tool for generating quiescent stem cells and cancer cells. In response to mTOR suppression, quiescent cancer cells dynamically change their proteome, triggering alternative non-canonical translation mechanisms. The shift to selective translation may have clinical relevance, since quiescent tumor cells can acquire new phenotypical features. This review provides new insights into the patterns of mTOR functioning in quiescent cancer cells, enhancing our current understanding of the biology of latent metastasis.
Hypoxia-induced immortalization of primary cells depends on Tfcp2L1 expression
Authors: Otero-Albiol D. , Santos-Pereira J. M. , Lucena-Cacace A. , Clemente-González C. , Muñoz-Galvan S. , Yoshida Y. , Carnero A. 
Published: February 2024

AbstractCellular senescence is a stress response mechanism that induces proliferative arrest. Hypoxia can bypass senescence and extend the lifespan of primary cells, mainly by decreasing oxidative damage. However, how hypoxia promotes these effects prior to malignant transformation is unknown. Here we observed that the lifespan of mouse embryonic fibroblasts (MEFs) is increased when they are cultured in hypoxia by reducing the expression of p16INK4a, p15INK4b and p21Cip1. We found that proliferating MEFs in hypoxia overexpress Tfcp2l1, which is a main regulator of pluripotency and self-renewal in embryonic stem cells, as well as stemness genes including Oct3/4, Sox2 and Nanog. Tfcp2l1 expression is lost during culture in normoxia, and its expression in hypoxia is regulated by Hif1α. Consistently, its overexpression in hypoxic levels increases the lifespan of MEFs and promotes the overexpression of stemness genes. ATAC-seq and Chip-seq experiments showed that Tfcp2l1 regulates genes that control proliferation and stemness such as Sox2, Sox9, Jarid2 and Ezh2. Additionally, Tfcp2l1 can replicate the hypoxic effect of increasing cellular reprogramming. Altogether, our data suggest that the activation of Tfcp2l1 by hypoxia contributes to immortalization prior to malignant transformation, facilitating tumorigenesis and dedifferentiation by regulating Sox2, Sox9, and Jarid2.
Marine protected areas promote stability of reef fish communities under climate warming
Authors: Benedetti-Cecchi Lisandro , Bates Amanda E. , Strona Giovanni , Bulleri Fabio , Horta e Costa Barbara , Edgar Graham J. , Hereu Bernat , Reed Dan C. , Stuart-Smith Rick D. , Barrett Neville S. , Kushner David J. , Emslie Michael J. , García-Charton Jose Antonio , Gonçalves Emanuel J. , Aspillaga Eneko 
Published: February 2024

AbstractProtection from direct human impacts can safeguard marine life, yet ocean warming crosses marine protected area boundaries. Here, we test whether protection offers resilience to marine heatwaves from local to network scales. We examine 71,269 timeseries of population abundances for 2269 reef fish species surveyed in 357 protected versus 747 open sites worldwide. We quantify the stability of reef fish abundance from populations to metacommunities, considering responses of species and functional diversity including thermal affinity of different trophic groups. Overall, protection mitigates adverse effects of marine heatwaves on fish abundance, community stability, asynchronous fluctuations and functional richness. We find that local stability is positively related to distance from centers of high human density only in protected areas. We provide evidence that networks of protected areas have persistent reef fish communities in warming oceans by maintaining large populations and promoting stability at different levels of biological organization.
Understanding activity-stability tradeoffs in biocatalysts by enzyme proximity sequencing
Authors: Vanella Rosario , Küng Christoph , Schoepfer Alexandre A. , Doffini Vanni , Ren Jin , Nash Michael A. 
Published: February 2024

AbstractUnderstanding the complex relationships between enzyme sequence, folding stability and catalytic activity is crucial for applications in industry and biomedicine. However, current enzyme assay technologies are limited by an inability to simultaneously resolve both stability and activity phenotypes and to couple these to gene sequences at large scale. Here we present the development of enzyme proximity sequencing, a deep mutational scanning method that leverages peroxidase-mediated radical labeling with single cell fidelity to dissect the effects of thousands of mutations on stability and catalytic activity of oxidoreductase enzymes in a single experiment. We use enzyme proximity sequencing to analyze how 6399 missense mutations influence folding stability and catalytic activity in a D-amino acid oxidase from Rhodotorula gracilis. The resulting datasets demonstrate activity-based constraints that limit folding stability during natural evolution, and identify hotspots distant from the active site as candidates for mutations that improve catalytic activity without sacrificing stability. Enzyme proximity sequencing can be extended to other enzyme classes and provides valuable insights into biophysical principles governing enzyme structure and function.
Zirconium and hafnium catalyzed C–C single bond hydroboration
Authors: Li Sida , Jiao Haijun , Shu Xing-Zhong , Wu Lipeng 
Published: February 2024

AbstractSelective cleavage and subsequent functionalization of C−C single bonds present a fundamental challenge in synthetic organic chemistry. Traditionally, the activation of C−C single bonds has been achieved using stoichiometric transition-metal complexes. Recently, examples of catalytic processes were developed in which use is made of precious metals. However, the use of inexpensive and Earth-abundant group IV metals for catalytic C−C single-bond cleavage is largely underdeveloped. Herein, the zirconium-catalyzed C−C single-bond cleavage and subsequent hydroboration reactions is realized using Cp2ZrCl2 as a catalytic system. A series of structures of various γ-boronated amines are readily obtained, which are otherwise difficult to obtain. Mechanistic studies disclose the formation of a N–ZrIV species, and then a β-carbon elimination route is responsible for C–C single bond activation. Besides zirconium, hafnium exhibits a similar performance for this transformation.
Synthetic microbe-to-plant communication channels
Authors: Boo Alice , Toth Tyler , Yu Qiguo , Pfotenhauer Alexander , Fields Brandon D. , Lenaghan Scott C. , Stewart C. Neal , Voigt Christopher A. 
Published: February 2024

AbstractPlants and microbes communicate to collaborate to stop pests, scavenge nutrients, and react to environmental change. Microbiota consisting of thousands of species interact with each other and plants using a large chemical language that is interpreted by complex regulatory networks. In this work, we develop modular interkingdom communication channels, enabling bacteria to convey environmental stimuli to plants. We introduce a “sender device” in Pseudomonas putida and Klebsiella pneumoniae, that produces the small molecule p-coumaroyl-homoserine lactone (pC-HSL) when the output of a sensor or circuit turns on. This molecule triggers a “receiver device” in the plant to activate gene expression. We validate this system in Arabidopsis thaliana and Solanum tuberosum (potato) grown hydroponically and in soil, demonstrating its modularity by swapping bacteria that process different stimuli, including IPTG, aTc and arsenic. Programmable communication channels between bacteria and plants will enable microbial sentinels to transmit information to crops and provide the building blocks for designing artificial consortia.
Comprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies
Authors: Wang Bofei , Reville Patrick K. , Yassouf Mhd Yousuf , Jelloul Fatima Z. , Ly Christopher , Desai Poonam N. , Wang Zhe , Borges Pamella , Veletic Ivo , Dasdemir Enes , Burks Jared K. , Tang Guilin , Guo Shengnan , Garza Araceli Isabella , Nasnas Cedric , Vaughn Nicole R. , Baran Natalia , Deng Qing , Matthews Jairo , Gunaratne Preethi H. , Antunes Dinler A. , Ekmekcioglu Suhendan , Sasaki Koji , Garcia Miriam B. , Cuglievan Branko , Hao Dapeng , Daver Naval , Green Michael R. , Konopleva Marina , Futreal Andrew , Post Sean M. , Abbas Hussein A. 
Published: February 2024

AbstractInterferon gamma (IFNγ) is a critical cytokine known for its diverse roles in immune regulation, inflammation, and tumor surveillance. However, while IFNγ levels were elevated in sera of most newly diagnosed acute myeloid leukemia (AML) patients, its complex interplay in AML remains insufficiently understood. We aim to characterize these complex interactions through comprehensive bulk and single-cell approaches in bone marrow of newly diagnosed AML patients. We identify monocytic AML as having a unique microenvironment characterized by IFNγ producing T and NK cells, high IFNγ signaling, and immunosuppressive features. IFNγ signaling score strongly correlates with venetoclax resistance in primary AML patient cells. Additionally, IFNγ treatment of primary AML patient cells increased venetoclax resistance. Lastly, a parsimonious 47-gene IFNγ score demonstrates robust prognostic value. In summary, our findings suggest that inhibiting IFNγ is a potential treatment strategy to overcoming venetoclax resistance and immune evasion in AML patients.
A framework for evaluating clinical artificial intelligence systems without ground-truth annotations
Authors: Kiyasseh Dani , Cohen Aaron , Jiang Chengsheng , Altieri Nicholas 
Published: February 2024

AbstractA clinical artificial intelligence (AI) system is often validated on data withheld during its development. This provides an estimate of its performance upon future deployment on data in the wild; those currently unseen but are expected to be encountered in a clinical setting. However, estimating performance on data in the wild is complicated by distribution shift between data in the wild and withheld data and the absence of ground-truth annotations. Here, we introduce SUDO, a framework for evaluating AI systems on data in the wild. Through experiments on AI systems developed for dermatology images, histopathology patches, and clinical notes, we show that SUDO can identify unreliable predictions, inform the selection of models, and allow for the previously out-of-reach assessment of algorithmic bias for data in the wild without ground-truth annotations. These capabilities can contribute to the deployment of trustworthy and ethical AI systems in medicine.
Cellular reprogramming as a tool to model human aging in a dish
Authors: Pitrez Patricia R. , Monteiro Luis M. , Borgogno Oliver , Nissan Xavier , Mertens Jerome , Ferreira Lino 
Published: February 2024

AbstractThe design of human model systems is highly relevant to unveil the underlying mechanisms of aging and to provide insights on potential interventions to extend human health and life span. In this perspective, we explore the potential of 2D or 3D culture models comprising human induced pluripotent stem cells and transdifferentiated cells obtained from aged or age-related disorder-affected donors to enhance our understanding of human aging and to catalyze the discovery of anti-aging interventions.
A Phase II trial of alternating osimertinib and gefitinib therapy in advanced EGFR-T790M positive non-small cell lung cancer: OSCILLATE
Authors: Tan Lavinia , Brown Chris , Mersiades Antony , Lee Chee Khoon , John Thomas , Kao Steven , Newnham Genni , O’Byrne Kenneth , Parakh Sagun , Bray Victoria , Jasas Kevin , Yip Sonia , Wong Stephen Q. , Ftouni Sarah , Guinto Jerick , Chandrashekar Sushma , Clarke Stephen , Pavlakis Nick , Stockler Martin R. , Dawson Sarah-Jane , Solomon Benjamin J. 
Published: February 2024

AbstractIn this phase II, single arm trial (ACTRN12617000720314), we investigate if alternating osimertinib and gefitinib would delay the development of resistance to osimertinib in advanced, non-small cell lung cancer (NSCLC) with the epidermal growth factor receptor (EGFR) T790M mutation (n = 47) by modulating selective pressure on resistant clones. The primary endpoint is progression free-survival (PFS) rate at 12 months, and secondary endpoints include: feasibility of alternating therapy, overall response rate (ORR), overall survival (OS), and safety. The 12-month PFS rate is 38% (95% CI 27.5–55), not meeting the pre-specified primary endpoint. Serial circulating tumor DNA (ctDNA) analysis reveals decrease and clearance of the original activating EGFR and EGFR-T790M mutations which are prognostic of clinical outcomes. In 73% of participants, loss of T790M ctDNA is observed at progression and no participants have evidence of the EGFR C797S resistance mutation following the alternating regimen. These findings highlight the challenges of treatment strategies designed to modulate clonal evolution and the clinical importance of resistance mechanisms beyond suppression of selected genetic mutations in driving therapeutic escape to highly potent targeted therapies.