bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characteristics of High-Quality Multi-Hospital Health Systems Performing Major Cancer Surgery
Authors: Schaefer Sara L. , Kalata Stanley , Nuliyalu Ushapoorna , Ibrahim Andrew M. , Nathan Hari 
Published: September 2024

Objective:
To identify characteristics associated with high- and low-quality multi-hospital systems for major cancer surgery

Background:
Although multi-hospital health systems provide most inpatient healthcare in the US, our understanding of how these systems can optimize surgical quality among their hospitals remains limited. Identifying the structural characteristics (e.g., number of hospitals, procedural volume, geographic dispersion) that distinguish high- and low-quality systems may inform actionable strategies to improve surgical quality.

Methods:
We conducted a retrospective cross-sectional observational study of 270,491 Medicare beneficiaries (2016-2020) undergoing major cancer surgery at a multi-hospital health system. Systems were classified into quartiles of quality based on risk- and reliability-adjusted rates of 30-day mortality using a hierarchical multivariable logistical regression model to adjust for patient, procedural, and hospital factors.

Results:
The adjusted 30-day operative mortality rate in the highest- versus lowest-quality quartile of systems was 1.7% versus 3.1%,(P<0.001). High-quality systems had fewer hospitals per system (median [IQR], number of system hospitals, 5 [3-11] vs. 12 [8-30];P<0.001), with each performing more procedures per hospital (median [IQR] annual procedure volume, 104 [52-218] vs. 45 [22-90];P<0.001). High-quality systems were also more geographically concentrated (median [IQR] maximum distance between hospitals, 62 [19-194] vs. 321 [91-1125] miles;P<0.001). Furthermore, high-quality systems demonstrated less variation in quality between hospitals (mean [SD] within-system absolute variation in mortality, 0.8% [0.3%] vs. 2.6% [1.0%];P<0.001).

Conclusions:
The highest-quality multi-hospital systems had fewer, more geographically concentrated hospitals, with each performing more procedures per hospital. Among the highest-quality systems, diverse system phenotypes were represented, suggesting the potential to overcome structural limitations and achieve high quality.
Angiotensin-converting enzyme inhibition and Alzheimer’s disease: Findings from proteome-wide Mendelian randomization and a large prospective cohort study
Authors: Huang Peiyuan , Tang Haibo , Feng Zeying , Stergiakouli Evie , Gaunt Tom R , Zheng Jie , Lu Yao 
Published: September 2024

ABSTRACTBackgroundWe aimed to provide clinically translatable insights for drug discovery, repurposing, and vigilance for preventing Alzheimer’s disease (AD) by integrating genetic and “real-world” drug use data.MethodsProteome-wide Mendelian randomization (MR) analysis was conducted to identify plasma proteins causally related to AD risk using the largest summary-level data to date, followed by colocalization and multi-omic validation analyses (on the gene expression, alternative splicing, and DNA methylation levels in blood and brain, respectively) to prioritize potential druggable targets. We also replicated our MR findings using additional genetic data and, where appropriate, performed multivariable MR for the prioritized findings. Conventional observational analysis using the data from UK Biobank, a large prospective cohort, was performed to provide further clinical implications for our genetic findings.ResultsMR analysis identified 15 plasma proteins with putative causal effects on AD risk. Of them, inhibition of angiotensin-converting enzyme (ACE) was found to increase the risk of AD (OR 1.10, 95% CI 1.08-1.14), which was likely independent of blood pressure as suggested by multivariable MR. Observational analysis in UK Biobank showed a higher incidence (HR 1.24, 95% CI 1.01-1.52) of AD among regular users of ACE inhibitors (ACEI), compared with the counterpart angiotensin receptor blocker users.ConclusionsIn addition to expanding the understanding of druggable targets for AD prevention, our findings highlighted the potential risk of AD associated with the use of ACEIs, a widely prescribed antihypertensive medication, suggesting the need for caution in clinical practice and further research on the effect of antihypertensives on neurodegenerative diseases.
Rigorous (in)validation of ecological models
Authors: Song Chuliang , Levine Jonathan M. 
Published: September 2024

AbstractThe complexity of ecosystems poses a formidable challenge for confidently invalidating ecological models, as current practices struggle to distinguish model inadequacies from the confounding effects of unobserved biotic or abiotic factors. The prevailing inability to falsify models has resulted in an accumulation of models but not an accumulation of confidence. Here, we introduce a new approach rooted in queueing theory, termed thecovariance criteria, that establishes a rigorous test for model validity based on covariance relationships between observable quantities. These criteria set a high bar for models to pass by specifying necessary conditions that must hold regardless of unobserved factors. We demonstrate the broad applicability and discriminatory power of the covariance criteria by applying them to three long-standing challenges in ecological theory: resolving competing models of predator-prey functional responses, disentangling ecological and evolutionary dynamics in systems with rapid evolution, and detecting the often-elusive influence of higher-order species interactions. Across these diverse case studies, the covariance criteria consistently rule out inadequate models, while building strong confidence in those that provide strategically useful approximations. The covariance criteria approach is mathematically rigorous, computationally efficient, and often non-parametric, making it immediately applicable to existing data and models.
The use of 3D-printers as plotters opens up a new world in performing 2D migration analyses
Authors: Köppe Hanjo , Richert Magnus G. , Singer Debora , Köppe Jorn , Köppe Mattes , Tzvetkov Mladen , Schroeder Henry W. S. , Bekeschus Sander , Bien-Möller Sandra 
Published: September 2024

AbstractScratch wound healing assays remain one of the most commonly used 2D migration assay to obtain a broad overview of the migration behavior of cultured cells. They are easy to perform and cost effective, but yet not standardized in terms of the geometric dimensions of the scratch, e.g. consistency of the scratch width and straightness of the line, especially when performed manually. Furthermore, conventional scratch assays only include a single scratch, which leads to a limited evaluation of a restricted cell population within the culture plates, but not of all cells grown in the chamber. There are commercially available ‘scratch-makers’ which are highly expensive and yet lack advanced functions such as scratching complex patterns. However, such complex scratch formations would make it possible to assess the entire cell population in a chamber and to evaluate the influence of the scratch itself, e.g. with regard to the regulation of migration-associated proteins. We have therefore developed for the first time a method that not only standardizes the scratch dimensions for different pipette tips, but also gives the opportunity to scratch any conceivable 2D shape by using 3D printers as 2D plotters. This open-source and low-cost system can be performed with any plate format from any manufacture under culture hood conditions. The 2D plotter-based method developed and validated by us provides highly reproducible and consistent scratch parameters forin vitromigration analyses.
IgGM: A Generative Model for Functional Antibody and Nanobody Design
Authors: Wang Rubo , Wu Fandi , Gao Xingyu , Wu Jiaxiang , Zhao Peilin , Yao Jianhua 
Published: September 2024

AbstractImmunoglobulins are crucial proteins produced by the immune system to identify and bind to foreign substances, playing an essential role in shielding organisms from infections and diseases. Designing specific antibodies opens new pathways for disease treatment. With the rise of deep learning, AI-driven drug design has become possible, leading to several methods for antibody design. However, many of these approaches require additional conditions that differ from real-world scenarios, making it challenging to incorporate them into existing antibody design processes. Here, we introduce IgGM, a generative model for the de novo design of immunoglobulins with functional specificity. IgGM produces antibody sequences and structures simultaneously for a given antigen, consisting of three core components: a pre-trained language model for extracting sequence features, a feature learning module for identifying pertinent features, and a prediction module that outputs designed antibody sequences and the predicted complete antibody-antigen complex structure. IgGM has demonstrated its effectiveness in not only predicting structures but also designing novel antibodies and nanobodies. This makes it highly applicable in a wide range of practical situations related to antibody and nanobody design.1
Selective loss of Y chromosomes in lung adenocarcinoma modulates the tumor immune environment through cancer/testis antigens
Authors: Fischer Jonas , Shutta Katherine H. , Chen Chen , Fanfani Viola , Saha Enakshi , Mandros Panagiotis , Ben Guebila Marouen , Xiu Joanne , Nieva Jorge , Liu Stephen , Uprety Dipesh , Spetzler David , Lopes-Ramos Camila M. , DeMeo Dawn , Quackenbush John 
Published: September 2024

AbstractThere is increasing recognition that the sex chromosomes, X and Y, play an important role in health and disease that goes beyond the determination of biological sex. Loss of the Y chromosome (LOY) in blood, which occurs naturally in aging men, has been found to be a driver of cardiac fibrosis and heart failure mortality. LOY also occurs in most solid tumors in males and is often associated with worse survival, suggesting that LOY may give tumor cells a growth or survival advantage. We analyzed LOY in lung adenocarcinoma (LUAD) using both bulk and single-cell expression data and found evidence suggesting that LOY affects the tumor immune environment by altering cancer/testis antigen expression and consequently facilitating tumor immune evasion. Analyzing immunotherapy data, we show that LOY and changes in expression of particular cancer/testis antigens are associated with response to pembrolizumab treatment and outcome, providing a new and powerful biomarker for predicting immunotherapy response in LUAD tumors in males.
Fasting is required for many of the benefits of calorie restriction in the 3xTg mouse model of Alzheimer’s disease
Authors: Babygirija Reji , Han Jessica H. , Sonsalla Michelle M. , Matoska Ryan , Calubag Mariah F. , Green Cara L. , Tobon Anna , Yeh Chung-Yang , Vertein Diana , Schlorf Sophia , Illiano Julia , Liu Yang , Grunow Isaac , Rigby Michael J. , Puglielli Luigi , Harris David A. , Denu John M. , Lamming Dudley W. 
Published: September 2024

AbstractCaloric restriction (CR) is a widely recognized geroprotective intervention that slows or prevents Alzheimer’s disease (AD) in animal models. CR is typically implemented via feeding mice a single meal per day; as CR mice rapidly consume their food, they are subject to a prolonged fast between meals. While CR has been shown to improve metabolic and cognitive functions and suppress pathological markers in AD mouse models, the specific contributions of fasting versus calorie reduction remains unclear. Here, we investigated the contribution of fasting and energy restriction to the beneficial effects of CR on AD progression. To test this, we placed 6-month-old 3xTg mice on one of several diet regimens, allowing us to dissect the effects of calories and fasting on metabolism, AD pathology, and cognition. We find that energy restriction alone, without fasting, was sufficient to improve glucose tolerance and reduce adiposity in both sexes, and to reduce Aβ plaques and improve aspects of cognitive performance in females. However, we find that a prolonged fast between meals is necessary for many of the benefits of CR, including improved insulin sensitivity, reduced phosphorylation of tau, decreased neuroinflammation, inhibition of mTORC1 signaling, and activation of autophagy, as well as for the full cognitive benefits of CR. Finally, we find that fasting is essential for the benefits of CR on survival in male 3xTg mice. Overall, our results demonstrate that fasting is required for the full benefits of a CR diet on the development and progression of AD in 3xTg mice, and suggest that both when and how much we eat influences the development and progress of AD.
Loss of PMR4 callose synthase results in salicylic acid-independent and broad-spectrum resistance to clubroot inArabidopsisandBrassica napus
Authors: Luo Brian , Wang Lipu , Wen Rui , Yang Kun , Liu Xunjia , Tu Jiangying , Dumonceaux Tim , Wei Yangdou , Peng Garry , Xiao Wei 
Published: September 2024

AbstractThe clubroot disease caused by protistPlasmodiophora brassicaeis one of the most important diseases of Brassica crops. Growing clubroot-resistant cultivars remains the most effective and practical approach to managing clubroot disease. However, resistance gene-mediated immunity is rapidly overcome in the field when new pathotypes arise. In this study, we identifiedPMR4as a potential gene target for creating a novel clubroot-resistant source. RecessivePMR4mutations inArabidopsis thalianaconferred broad-spectrum resistance to multipleP. brassicaepathotypes, independent of salicylic acid-mediated plant immunity. CRISPR/Cas9-mediated gene-editing was employed to create mutations in twoPMR4orthologs in theB. napusgenome, and resulting homozygous mutants exhibited dual resistance to powdery mildew and clubroot. PMR4 is required for the callose deposition at wound and powdery mildew infection sites in leaves. This study reveals that callose deposition in roots is induced byP. brassicaeinfection and requires PMR4. It appears that the clubroot disease progression is arrested at the primary-to-secondary infection phase inpmr4-1mutants. Together, this study demonstrates thatPMR4-encoded callose synthase is a host susceptibility factor required forP. brassicaeto complete its life cycle, and thatPMR4can be targeted against both powdery mildew and clubroot diseases in Brassica crops.
miR-21: A therapeutic target for delaying severe liver disease and hepatocellular carcinoma in high-fat-diet-fed mice
Authors: Jagtap Urmila , Quan Anan , Ono Yuho , Lee Jonathan , Shen Kylie A. , Manakov Sergei , Szabo Gyongyi , Nasser Imad , Slack Frank J. 
Published: September 2024

AbstractLiver disease, including hepatocellular carcinoma (HCC), is a major global health concern, claiming approximately 2 million lives worldwide annually, yet curative treatments remain elusive. In this study, we aimed to investigate the role of microRNA-21-5p (miR-21) in metabolic dysfunction-associated steatotic liver disease (previously NAFLD), metabolic-associated steatohepatitis (previously NASH), and HCC within the context of a Western high-fat diet, without additional choline (HFD) and offering potential therapeutic insights. We found that reduced miR-21 levels correlated with liver disease progression in WT mice fed on HFD, while miR-21 knockout mice showed exacerbated metabolic dysfunction, including obesity, hepatomegaly, hyperglycemia, insulin resistance, steatosis, fibrosis, and HCC. Our study reveals that miR-21 plays a protective role in metabolic syndrome and in the progression of liver disease to cancer. MiR-21 directly targetsTransforming growth factor beta-induced(Tgfbi), a gene also known to be significantly upregulated and a potential oncogene in HCC. Further, our study showed that intervention with the administration of a miR-21 mimic in WT livers effectively improves insulin sensitivity, steatosis, fibrosis,Tgfbiexpression and tumor burden in HFD conditions. These findings indicate that miR-21 could serve as an effective strategy to delay or prevent liver disease in high-fat-diet environments.SignificanceOur study demonstrates in vivo that miR-21 has protective functions in the broad spectrum of high-fat diet-based, progressive liver disease and cancer, and we show potential therapeutic value of a microRNA-21 mimic.Graphical abstract
How interactions between temperature and resources scale from populations to communities
Authors: Kremer Colin T. , Thomas Mridul K. , Klausmeier Christopher A. , Litchman Elena 
Published: September 2024

AbstractTemperature and resources are fundamental factors that determine the ability of organisms to function and survive, while influencing their development, growth, and reproduction. Major bodies of ecological theory have emerged, largely independently, to address temperature and resource effects. It remains a major challenge to unite these ideas and determine the interactive effects of temperature and resources on ecological patterns and processes, and their consequences across ecological scales. Here, we propose a simple, physiologically motivated model capturing the interactive effects of temperature and resources (including inorganic nutrients and light) on the growth of microbial ectotherms over multiple ecological scales. From this model we derive a set of key predictions. At the population level, we predict (i) interactive effects of resource limitation on thermal traits, (ii) consistent differences in the temperature sensitivity of auto- and heterotrophs, and (iii) the existence of specific tradeoffs between traits that determine the shape of thermal performance curves. At the community level, we derive predictions for (iv) how limitation by nutrients and light can change the relationship between temperature and productivity. All four predictions are upheld, based on our analyses of a large compilation of laboratory data on microbial growth, as well as field experiments with marine phytoplankton communities. Collectively, our modeling framework provides a new way of thinking about the interplay between two fundamental aspects of life — temperature and resources — and how they constrain and structure ecological properties across scales. Providing links between population and community responses to simultaneous changes in abiotic factors is essential to anticipating the multifaceted effects of global change.
A novel OsIAA3-OsARF16-OsBUL1module regulates grain size in rice
Authors: Xian Fengjun , Liu Shuya , Huang Jishuai , Xie Bin , Zhu Lin , Zhang Qiannan , Lv Chen , Xu Yimeng , Zhang Xinrong , Hu Jun 
Published: September 2024

AbstractAuxin plays an important role in almost every aspect of plant growth and development. However, the molecular mechanism underlying the control of grain size via auxin signaling pathways is still obscure. Here, we reported that the riceAux/IAAgeneOsIAA3positively regulates grain size by promoting the cell expansion and proliferation of spikelet hulls. OsIAA3 interacted with 11 OsARFs, among which the interaction with OsARF16 was the strongest. Knockout ofosarf16led to smaller grain with decreased grain length, grain width, grain thickness and 1,000-grain weight. Meanwhile, transgenic plants overexpressingOsARF16produced apparently bigger grain with increased grain length and 1,000-grain weight. Additionally,OsBUL1, which positive regulates grain size by promoting cell expansion is a direct target gene ofOsARF16. Results demonstrated that the interaction between OsIAA3 and OsARF16 repressed the transcriptional activation of OsARF16 onOsBUL1. Taken together, our study revealed a novel OsIAA3-OsARF16-OsBUL1module which regulates grain size, enriching the molecular mechanism of auxin signaling pathway involved in regulating grain size.
A Paradoxical Tumor Antigen Specific Response in the Liver
Authors: Trehan Rajiv , Zhu Xiao Bin , Huang Patrick , Wang Xin , Soliman Marlaine , Strepay Dillon , Nur Amran , Kedei Noemi , Arhin Martin , Ghabra Shadin , Rodríguez-Matos Francisco , Benmebarek Mohamed-Reda , Ma Chi , Korangy Firouzeh , Greten Tim F. 
Published: September 2024

AbstractFunctional tumor-specific CD8+ T cells are essential for an effective anti-tumor immune response and the efficacy of immune checkpoint inhibitor therapy. In comparison to other organ sites, we found higher numbers of tumor-specific CD8+ T cells in primary, metastatic liver tumors in murine tumor models. Despite their abundance, CD8+ T cells in the liver displayed an exhausted phenotype. Depletion of CD8+ T cells showed that liver tumor-reactive CD8+ T failed to control liver tumors but was effective against subcutaneous tumors. Similarly, analysis of single-cell RNA sequencing data from patients showed a higher frequency of exhausted tumor-reactive CD8+ T cells in liver metastasis compared to paired primary colon cancer. High-dimensional, multi-omic analysis combining proteomic CODEX and scRNA-seq data revealed enriched interaction of SPP1+ macrophages and CD8+ tumor-reactive T cells in profibrotic, alpha-SMA rich regions in the liver. Liver tumors grew less in Spp1-/-mice and the tumor-specific CD8+ T cells were less exhausted. Differential pseudotime trajectory inference analysis revealed extrahepatic signaling promoting an intermediate cell (IC) population in the liver, characterized by co-expression of VISG4, CSF1R, CD163, TGF-βR, IL-6R, SPP1. scRNA-seq of a third data set of premetastatic adenocarcinoma showed that enrichment of this population may predict liver metastasis. Our data suggests a mechanism by which extrahepatic tumors facilitate the formation of liver metastasis by promoting an IC population inhibiting tumor-reactive CD8+ T cell function.
DiffPaSS – High-performance differentiable pairing of protein sequences using soft scores
Authors: Lupo Umberto , Sgarbossa Damiano , Milighetti Martina , Bitbol Anne-Florence 
Published: September 2024

AbstractIdentifying interacting partners from two sets of protein sequences has important applications in computational biology. Interacting partners share similarities across species due to their common evolutionary history, and feature correlations in amino acid usage due to the need to maintain complementary interaction interfaces. Thus, the problem of finding interacting pairs can be formulated as searching for a pairing of sequences that maximizes a sequence similarity or a coevolution score. Several methods have been developed to address this problem, applying different approximate optimization methods to different scores. We introduce DiffPaSS, a differentiable framework for flexible, fast, and hyperparameter-free optimization for pairing interacting biological sequences, which can be applied to a wide variety of scores. We apply it to a benchmark prokaryotic dataset, using mutual information and neighbor graph alignment scores. DiffPaSS outperforms existing algorithms for optimizing the same scores. We demonstrate the usefulness of our paired alignments for the prediction of protein complex structure. DiffPaSS does not require sequences to be aligned, and we also apply it to non-aligned sequences from T cell receptors.