bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mid‐Air Collisions Control the Wavelength of Aeolian Sand Ripples
Authors: Huo Xinghui , Herrmann Hans J. , Zhang Jie , Huang Ning 
Published: March 2024

AbstractThe wavelength of aeolian sand ripples increases with wind velocity, but the cause for this increase remained unclear until now. Using numerical simulations, we find that the relationship between the wind strength and the initial wavelength disappears without mid‐air collisions, which means that mid‐air collisions crucially contribute to the initial wavelength of ripples. As wind strength increases, the average hop length of non‐colliding particles decreases. Affected by the bed surface topography and the non‐uniform mid‐air colliding probability along the wavy surface, non‐colliding particles cause a surface modulated erosion/deposition flux. The first order contribution of the flux fluctuation destabilizes the original bed surface and has a wind‐dependent phase shift with respect to the surface profile. This phase shift leads to an initial wavelength that increases with wind velocity. Based on these findings we derive the scaling law for the initial wavelength of aeolian sand ripples, which agrees well with experimental results. A weak non‐linear relationship between ripple wavelength and wind velocity has been found, especially for large wind strengths.
Optimal Allocation Strategies of Plant Calcium on Qinghai–Tibetan Plateau
Authors: Jiao Chaolian , Zhang Jiahui , Wang Xiaochun , He Nianpeng 
Published: March 2024

AbstractCalcium (Ca) is an essential nutrient for plant growth and development. As Ca plays crucial roles in plant structure and signaling, its allocation strategies among organs can reflect the optimization of plant functions and responses to the environment. However, the allocation strategies and spatial variation of plant Ca at the community level have not been systematically determined on a large scale despite their potential link to ecosystem functions. Here, we mapped community‐level Ca content and density (1 × 1 km) using grid‐investigated data on leaves, branches, trunks, and roots from 680 sampling sites on the Qinghai–Tibetan Plateau (TP). Specifically, the Ca content and density of the leaves, branches, trunks, and roots of TP plants were 10.90, 6.09, 1.85, and 15.62 mg g−1 and 3.29, 17.10, 12.27, and 12.06 g m−2, respectively. Importantly, plant adopted optimal allocation strategies with allocating more Ca to roots in stressed ecosystems to maintain survival while more Ca to leaves in suitable forests for growth, that is the proposed survival/growth‐driven allocation hypothesis. Furthermore, plants optimally absorbed more nutrients in stressed environments for defense, as demonstrated by the higher Ca content and lower Ca use efficiency in deserts and grasslands than in forests. Furthermore, the strong evidence for the proposed hypothesis was the spatial pattern of plant Ca content decreasing from the northwest to the southeast. Our findings reveal the optimal nutrient allocation strategies and provide data support (Ca content and density) for assessing plant nutrient status in different types of ecosystems.
Bayesian interim analysis for prospective randomized studies: reanalysis of the acute myeloid leukemia HOVON 132 clinical trial
Authors: van der Maas Niek G. , Versluis Jurjen , Nasserinejad Kazem , van Rosmalen Joost , Pabst Thomas , Maertens Johan , Breems Dimitri , Manz Markus , Cloos Jacqueline , Ossenkoppele Gert J. , Floisand Yngvar , Gradowska Patrycja , Löwenberg Bob , Huls Gerwin , Postmus Douwe , Pignatti Francesco , Cornelissen Jan J. 
Published: March 2024

AbstractRandomized controlled trials (RCTs) are the gold standard to establish the benefit-risk ratio of novel drugs. However, the evaluation of mature results often takes many years. We hypothesized that the addition of Bayesian inference methods at interim analysis time points might accelerate and enforce the knowledge that such trials may generate. In order to test that hypothesis, we retrospectively applied a Bayesian approach to the HOVON 132 trial, in which 800 newly diagnosed AML patients aged 18 to 65 years were randomly assigned to a “7 + 3” induction with or without lenalidomide. Five years after the first patient was recruited, the trial was negative for its primary endpoint with no difference in event-free survival (EFS) between experimental and control groups (hazard ratio [HR] 0.99, p = 0.96) in the final conventional analysis. We retrospectively simulated interim analyses after the inclusion of 150, 300, 450, and 600 patients using a Bayesian methodology to detect early lack of efficacy signals. The HR for EFS comparing the lenalidomide arm with the control treatment arm was 1.21 (95% CI 0.81–1.69), 1.05 (95% CI 0.86–1.30), 1.00 (95% CI 0.84–1.19), and 1.02 (95% CI 0.87–1.19) at interim analysis 1, 2, 3 and 4, respectively. Complete remission rates were lower in the lenalidomide arm, and early deaths more frequent. A Bayesian approach identified that the probability of a clinically relevant benefit for EFS (HR < 0.76, as assumed in the statistical analysis plan) was very low at the first interim analysis (1.2%, 0.6%, 0.4%, and 0.1%, respectively). Similar observations were made for low probabilities of any benefit regarding CR. Therefore, Bayesian analysis significantly adds to conventional methods applied for interim analysis and may thereby accelerate the performance and completion of phase III trials.
Regulatory T cells expressing CD19-targeted chimeric antigen receptor restore homeostasis in Systemic Lupus Erythematosus
Authors: Doglio M. , Ugolini A. , Bercher-Brayer C. , Camisa B. , Toma C. , Norata R. , Del Rosso S. , Greco R. , Ciceri F. , Sanvito F. , Casucci M. , Manfredi A. A. , Bonini C. 
Published: March 2024

AbstractSystemic Lupus Erythematosus (SLE) is a progressive disease leading to immune-mediated tissue damage, associated with an alteration of lymphoid organs. Therapeutic strategies involving regulatory T (Treg) lymphocytes, which physiologically quench autoimmunity and support long-term immune tolerance, are considered, as conventional treatment often fails. We describe here a therapeutic strategy based on Tregs overexpressing FoxP3 and harboring anti-CD19 CAR (Fox19CAR-Tregs). Fox19CAR-Tregs efficiently suppress proliferation and activity of B cells in vitro, which are relevant for SLE pathogenesis. In an humanized mouse model of SLE, a single infusion of Fox19CAR-Tregs restricts autoantibody generation, delay lymphopenia (a key feature of SLE) and restore the human immune system composition in lymphoid organs, without detectable toxicity. Although a short survival, SLE target organs appear to be protected. In summary, Fox19CAR-Tregs can break the vicious cycle leading to autoimmunity and persistent tissue damage, representing an efficacious and safe strategy allowing restoration of homeostasis in SLE.
High-throughput prediction of protein conformational distributions with subsampled AlphaFold2
Authors: Monteiro da Silva Gabriel , Cui Jennifer Y. , Dalgarno David C. , Lisi George P. , Rubenstein Brenda M. 
Published: March 2024

AbstractThis paper presents an innovative approach for predicting the relative populations of protein conformations using AlphaFold 2, an AI-powered method that has revolutionized biology by enabling the accurate prediction of protein structures. While AlphaFold 2 has shown exceptional accuracy and speed, it is designed to predict proteins’ ground state conformations and is limited in its ability to predict conformational landscapes. Here, we demonstrate how AlphaFold 2 can directly predict the relative populations of different protein conformations by subsampling multiple sequence alignments. We tested our method against nuclear magnetic resonance experiments on two proteins with drastically different amounts of available sequence data, Abl1 kinase and the granulocyte-macrophage colony-stimulating factor, and predicted changes in their relative state populations with more than 80% accuracy. Our subsampling approach worked best when used to qualitatively predict the effects of mutations or evolution on the conformational landscape and well-populated states of proteins. It thus offers a fast and cost-effective way to predict the relative populations of protein conformations at even single-point mutation resolution, making it a useful tool for pharmacology, analysis of experimental results, and predicting evolution.
Uncovering structural themes across cilia microtubule inner proteins with implications for human cilia function
Authors: Andersen Jens S. , Vijayakumaran Aaran , Godbehere Christopher , Lorentzen Esben , Mennella Vito , Schou Kenneth Bødtker 
Published: March 2024

AbstractCentrosomes and cilia are microtubule-based superstructures vital for cell division, signaling, and motility. The once thought hollow lumen of their microtubule core structures was recently found to hold a rich meshwork of microtubule inner proteins (MIPs). To address the outstanding question of how distinct MIPs evolved to recognize microtubule inner surfaces, we applied computational sequence analyses, structure predictions, and experimental validation to uncover evolutionarily conserved microtubule- and MIP-binding modules named NWE, SNYG, and ELLEn, and PYG and GFG-repeat by their signature motifs. These modules intermix with MT-binding DM10-modules and Mn-repeats in 24 Chlamydomonas and 33 human proteins. The modules molecular characteristics provided keys to identify elusive cross-species homologs, hitherto unknown human MIP candidates, and functional properties for seven protein subfamilies, including the microtubule seam-binding NWE and ELLEn families. Our work defines structural innovations that underpin centriole and axoneme assembly and demonstrates that MIPs co-evolved with centrosomes and cilia.
Trade-offs shaping transmission of sylvatic dengue and Zika viruses in monkey hosts
Authors: Hanley Kathryn A. , Cecilia Hélène , Azar Sasha R. , Moehn Brett A. , Gass Jordan T. , Oliveira da Silva Natalia I. , Yu Wanqin , Yun Ruimei , Althouse Benjamin M. , Vasilakis Nikos , Rossi Shannan L. 
Published: March 2024

AbstractMosquito-borne dengue (DENV) and Zika (ZIKV) viruses originated in Old World sylvatic (forest) cycles involving monkeys and canopy-living Aedes mosquitoes. Both viruses spilled over into human transmission and were translocated to the Americas, opening a path for spillback into Neotropical sylvatic cycles. Studies of the trade-offs that shape within-host dynamics and transmission of these viruses are lacking, hampering efforts to predict spillover and spillback. We infected a native, Asian host species (cynomolgus macaque) and a novel, American host species (squirrel monkey) with sylvatic strains of DENV-2 or ZIKV via mosquito bite. We then monitored aspects of viral replication (viremia), innate and adaptive immune response (natural killer (NK) cells and neutralizing antibodies, respectively), and transmission to mosquitoes. In both hosts, ZIKV reached high titers that translated into high transmission to mosquitoes; in contrast DENV-2 replicated to low levels and, unexpectedly, transmission occurred only when serum viremia was below or near the limit of detection. Our data reveal evidence of an immunologically-mediated trade-off between duration and magnitude of virus replication, as higher peak ZIKV titers are associated with shorter durations of viremia, and higher NK cell levels are associated with lower peak ZIKV titers and lower anti-DENV-2 antibody levels. Furthermore, patterns of transmission of each virus from a Neotropical monkey suggest that ZIKV has greater potential than DENV-2 to establish a sylvatic transmission cycle in the Americas.
Autophagy-mediated degradation of integumentary tapetum is critical for embryo pattern formation
Authors: Zhao Lin-lin , Chen Ru , Bai Ziyu , Liu Junyi , Zhang Yuhao , Zhong Yicheng , Sun Meng-xiang , Zhao Peng 
Published: March 2024

AbstractAutophagy modulates the degradation and recycling of intracellular materials and contributes to male gametophyte development and male fertility in plants. However, whether autophagy participates in seed development remains largely unknown. Here, we demonstrate that autophagy is crucial for timely programmed cell death (PCD) in the integumentary tapetum, the counterpart of anther tapetum, influencing embryo pattern formation and seed viability. Inhibition of autophagy resulted in delayed PCD of the integumentary tapetum and defects in embryo patterning. Cell-type-specific restoration of autophagic activities revealed that the integumentary tapetum plays a non-autonomous role in embryo patterning. Furthermore, high-throughput, comprehensive lipidomic analyzes uncovered an unexpected seed-developmental-stage-dependent role of autophagy in seed lipid metabolism: it contributes to triacylglycerol degradation before fertilization and to triacylglycerol biosynthesis after fertilization. This study highlights the critical role of autophagy in regulating timely integumentary tapetum PCD and reveals its significance in seed lipid metabolism and viability.
Replication study on the role of dopamine-dependent prefrontal reactivations in human extinction memory retrieval
Authors: Andres Elena , Chuan-Peng Hu , Gerlicher Anna M. V. , Meyer Benjamin , Tüscher Oliver , Kalisch Raffael 
Published: March 2024

AbstractEven after successful extinction, conditioned fear can return. Strengthening the consolidation of the fear-inhibitory safety memory formed during extinction is one way to counteract return of fear. In a previous study, we found that post-extinction L-DOPA administration improved extinction memory retrieval 24 h later. Furthermore, spontaneous post-extinction reactivations of a neural activation pattern evoked in the ventromedial prefrontal cortex (vmPFC) during extinction predicted extinction memory retrieval, L-DOPA increased the number of these reactivations, and this mediated the effect of L-DOPA on extinction memory retrieval. Here, we conducted a preregistered replication study of this work in healthy male participants. We confirm that spontaneous post-extinction vmPFC reactivations predict extinction memory retrieval. This predictive effect, however, was only observed 90 min after extinction, and was not statistically significant at 45 min as in the discovery study. In contrast to our previous study, we find no evidence that L-DOPA administration significantly enhances retrieval and that this is mediated by enhancement of the number of vmPFC reactivations. However, additional non-preregistered analyses reveal a beneficial effect of L-DOPA on extinction retrieval when controlling for the trait-like stable baseline levels of salivary alpha-amylase enzymatic activity. Further, trait salivary alpha-amylase negatively predicts retrieval, and this effect is reduced by L-DOPA treatment. Importantly, the latter findings result from non-preregistered analyses and thus further investigation is needed.
Adjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study
Authors: Lynce Filipa , Mainor Candace , Donahue Renee N. , Geng Xue , Jones Greg , Schlam Ilana , Wang Hongkun , Toney Nicole J. , Jochems Caroline , Schlom Jeffrey , Zeck Jay , Gallagher Christopher , Nanda Rita , Graham Deena , Stringer-Reasor Erica M. , Denduluri Neelima , Collins Julie , Chitalia Ami , Tiwari Shruti , Nunes Raquel , Kaltman Rebecca , Khoury Katia , Gatti-Mays Margaret , Tarantino Paolo , Tolaney Sara M. , Swain Sandra M. , Pohlmann Paula , Parsons Heather A. , Isaacs Claudine 
Published: March 2024

AbstractChemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints included the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that treatment with immunotherapy containing arms (nivolumab or a combination of nivolumab plus capecitabine) leads to an increase in PIS from baseline to week 6 compared with capecitabine alone, meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) is associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.
Synaptically-targeted long non-coding RNA SLAMR promotes structural plasticity by increasing translation and CaMKII activity
Authors: Espadas Isabel , Wingfield Jenna L. , Nakahata Yoshihisa , Chanda Kaushik , Grinman Eddie , Ghosh Ilika , Bauer Karl E. , Raveendra Bindu , Kiebler Michael A. , Yasuda Ryohei , Rangaraju Vidhya , Puthanveettil Sathyanarayanan 
Published: March 2024

AbstractLong noncoding RNAs (lncRNAs) play crucial roles in maintaining cell homeostasis and function. However, it remains largely unknown whether and how neuronal activity impacts the transcriptional regulation of lncRNAs, or if this leads to synapse-related changes and contributes to the formation of long-term memories. Here, we report the identification of a lncRNA, SLAMR, which becomes enriched in CA1-hippocampal neurons upon contextual fear conditioning but not in CA3 neurons. SLAMR is transported along dendrites via the molecular motor KIF5C and is recruited to the synapse upon stimulation. Loss of function of SLAMR reduces dendritic complexity and impairs activity-dependent changes in spine structural plasticity and translation. Gain of function of SLAMR, in contrast, enhances dendritic complexity, spine density, and translation. Analyses of the SLAMR interactome reveal its association with CaMKIIα protein through a 220-nucleotide element also involved in SLAMR transport. A CaMKII reporter reveals a basal reduction in CaMKII activity with SLAMR loss-of-function. Furthermore, the selective loss of SLAMR function in CA1 disrupts the consolidation of fear memory in male mice, without affecting their acquisition, recall, or extinction, or spatial memory. Together, these results provide new molecular and functional insight into activity-dependent changes at the synapse and consolidation of contextual fear.
S100A8/A9 as a prognostic biomarker with causal effects for post-acute myocardial infarction heart failure
Authors: Ma Jie , Li Yang , Li Ping , Yang Xinying , Zhu Shuolin , Ma Ke , Gao Fei , Gao Hai , Zhang Hui , Ma Xin-liang , Du Jie , Li Yulin 
Published: March 2024

AbstractHeart failure is the prevalent complication of acute myocardial infarction. We aim to identify a biomarker for heart failure post-acute myocardial infarction. This observational study includes 1062 and 1043 patients with acute myocardial infarction in the discovery and validation cohorts, respectively. The outcomes are in-hospital and long-term heart failure events. S100A8/A9 is screened out through proteomic analysis, and elevated circulating S100A8/A9 is independently associated with heart failure in discovery and validation cohorts. Furthermore, the predictive value of S100A8/A9 is superior to the traditional biomarkers, and the addition of S100A8/A9 improves the risk estimation using traditional risk factors. We finally report causal effect of S100A8/A9 on heart failure in three independent cohorts using Mendelian randomization approach. Here, we show that S100A8/A9 is a predictor and potentially causal medicator for heart failure post-acute myocardial infarction.
3D molecular generative framework for interaction-guided drug design
Authors: Zhung Wonho , Kim Hyeongwoo , Kim Woo Youn 
Published: March 2024

AbstractDeep generative modeling has a strong potential to accelerate drug design. However, existing generative models often face challenges in generalization due to limited data, leading to less innovative designs with often unfavorable interactions for unseen target proteins. To address these issues, we propose an interaction-aware 3D molecular generative framework that enables interaction-guided drug design inside target binding pockets. By leveraging universal patterns of protein-ligand interactions as prior knowledge, our model can achieve high generalizability with limited experimental data. Its performance has been comprehensively assessed by analyzing generated ligands for unseen targets in terms of binding pose stability, affinity, geometric patterns, diversity, and novelty. Moreover, the effective design of potential mutant-selective inhibitors demonstrates the applicability of our approach to structure-based drug design.
Stability, homogeneity and measurement uncertainty estimation of PVP-I solutions for the application on oro and nasopharynx against SARS-CoV-2
Authors: Moniruzzaman Md. , Razu Mamudul Hasan , Rahman Sad Al Rezwan , Kundu Nayan Kumer , Kamal Sabiha , Khan Mala 
Published: March 2024

AbstractAqueous solution containing different concentration (0.5, 0.6 and 1.0%) (w/v) of Polyvinyl pyrrolodon-Iodine (PVP-I) complex, a well-known antiseptic; is prepared and the stability and homogeneity of these solution is assessed as per the ICH Guidelines and International Harmonized Protocol respectively. The solutions were found to be sufficiently homogeneous and stable for a year at 25 °C (60%RH). Measurement uncertainty of the prepared PVP-I solutions were estimated by identifying possible sources of uncertainty using Ishikawa diagram and preparing uncertainty budget based on scope of calibration laboratory. The stable and homogenized PVP-I solution is to be used in a clinical trial for the application on oro and nasopharynx against novel SARS-CoV-2 Virus.
Flying fast improves aerodynamic economy of heavier birds
Authors: Bishop Charles M. , Halsey Lewis G. , Askew Graham N. 
Published: March 2024

AbstractA paradox of avian long-distance migrations is that birds must greatly increase their body mass prior to departure, yet this is presumed to substantially increase their energy cost of flight. However, here we show that when homing pigeons flying in a flock are loaded with ventrally located weight, both their heart rate and estimated energy expenditure rise by a remarkably small amount. The net effect is that costs per unit time increase only slightly and per unit mass they decrease. We suggest that this is because these homing flights are relatively fast, and consequently flight costs associated with increases in body parasite drag dominate over those of weight support, leading to an improvement in mass-specific flight economy. We propose that the relatively small absolute aerodynamic penalty for carrying enlarged fuel stores and flight muscles during fast flight has helped to select for the evolution of long-distance migration.