bluuebunny/crossref_metadata_2025_split huggingface dataset:
Artificial Intelligence to Reduce or Eliminate the Need for Gadolinium-Based Contrast Agents in Brain and Cardiac MRI
Authors: Mallio Carlo A. , Radbruch Alexander , Deike-Hofmann Katerina , van der Molen Aart J. , Dekkers Ilona A. , Zaharchuk Greg , Parizel Paul M. , Beomonte Zobel Bruno , Quattrocchi Carlo C. 
Published: May 2023

AbstractBrain and cardiac MRIs are fundamental noninvasive imaging tools, which can provide important clinical information and can be performed without or with gadolinium-based contrast agents (GBCAs), depending on the clinical indication. It is currently a topic of debate whether it would be feasible to extract information such as standard gadolinium-enhanced MRI while injecting either less or no GBCAs. Artificial intelligence (AI) is a great source of innovation in medical imaging and has been explored as a method to synthesize virtual contrast MR images, potentially yielding similar diagnostic performance without the need to administer GBCAs. If possible, there would be significant benefits, including reduction of costs, acquisition time, and environmental impact with respect to conventional contrast-enhanced MRI examinations. Given its promise, we believe additional research is needed to increase the evidence to make these AI solutions feasible, reliable, and robust enough to be integrated into the clinical framework. Here, we review recent AI studies aimed at reducing or replacing gadolinium in brain and cardiac imaging while maintaining diagnostic image quality.
A Novel Method to Reconstruct the Upper and Lower Jaws Using 3D-Custom-Made Titanium Implants
Authors: Al-Sukhun Jehad 
Published: May 2023

Background:
This paper presents a novel method of upper and lower jaw reconstruction using 3D-custom-made titanium implants with abutment-like projections. The implants were designed to rehabilitate the oral and facial shape, esthetic, function, and occlusion.

Patient and Method:
A 20-year-old boy was diagnosed as having Gorlin syndrome. The patient suffered from having large bony defects, after ablative multiple keratocysts resection, of the maxilla and mandible. The resulting defects were reconstructed with 3D-custom-made titanium implants. The implants with abutment-like projections were simulated, printed, and fabricated with a selective milling method based on computed tomography scan data.

Result:
There were no postoperative infections or foreign body reactions during the 1-year follow-up period.

Conclusion:
To the best of our knowledge, this is the first report on the use of 3D-custom-made titanium implants with abutment-like projections, attempting to rehabilitate the occlusion and overcome the limitations of custom-made implants in treating large bony defects of the maxilla and mandible.
The reports of my death are greatly exaggerated: An evaluation of futility cut points in massive transfusion
Authors: Clements Thomas W. , Van Gent Jan-Michael , Lubkin David E. , Wandling Michael W. , Meyer David E. , Moore Laura J. , Cotton Bryan A. 
Published: May 2023

BACKGROUND
Following COVID and the subsequent blood shortage, several investigators evaluated futility cut points in massive transfusion. We hypothesized that early aggressive use of damage-control resuscitation, including whole blood (WB), would demonstrate that these cut points of futility were significantly underestimating potential survival among patients receiving >50 U of blood in the first 4 hours.

METHODS
Adult trauma patients admitted from November 2017 to October 2021 who received emergency-release blood products in prehospital or emergency department setting were included. Deaths within 30 minutes of arrival were excluded. Total blood products were defined as total red blood cell, plasma, and WB in the field and in the first 4 hours after arrival. Patients were first divided into those receiving ≤50 or >50 U of blood in the first 4 hours. We then evaluated patients by whether they received any WB or received only component therapy. Thirty-day survival was evaluated for all included patients.

RESULTS
A total of 2,299 patients met the inclusion criteria (2,043 in ≤50 U, 256 in >50 U groups). While there were no differences in age or sex, the >50 U group was more likely to sustain penetrating injury (47% vs. 30%, p < 0.05). Patients receiving >50 U of blood had lower field and arrival blood pressure and larger prehospital and emergency department resuscitation volumes (p < 0.05). Patients in the >50 U group had lower survival than those in the ≤50 cohort (31% vs. 79%; p < 0.05). Patients who received WB (n = 1,291) had 43% increased odds of survival compared with those who received only component therapy (n = 1,008) (1.09–1.87, p = 0.009) and higher 30-day survival at transfusion volumes >50 U.

CONCLUSION
Patient survival rates in patients receiving >50 U of blood in the first 4 hours of care are as high as 50% to 60%, with survival still at 15% to 25% after 100 U. While responsible blood stewardship is critical, futility should not be declared based on high transfusion volumes alone.

LEVEL OF EVIDENCE
Therapeutic/Care Management; Level III.
Exploring the characteristics of successful prehospital trauma care teams: Insights from military trauma care simulations
Authors: Mitchnik Ilan Y. , Talmy Tomer , Feldman Barak , Almog Ofer , Fogel Itay 
Published: May 2023

BACKGROUND
Trauma care teams play a crucial role in determining the outcomes of trauma victims. The composition and training of these teams can vary. Our study seeks to examine the characteristics of successful military Advanced Life Support (ALS) teams and the factors that affect them.

METHODS
A retrospective study was conducted at the Israel Defense Force (IDF) Military Medical Academy throughout 2021, where prehospital medical teams were observed in trauma care simulations. Teams were led by ALS providers (military physicians or paramedics) trained in IDF Military Trauma Life Support. Demographic and training data were collected. Teams were categorized into high or subpar performance groups based on simulation scores. Specific skills were assessed by trauma instructors using a points system. Scores were compared between the groups and analyzed for correlations with demographic and training data.

RESULTS
Overall, 63 team simulations were analyzed, with teams led by a military paramedic in 78% of simulations. The mean overall simulation performance was 81% ±6.2, and there were no differences in scores of single or multicasualty simulations. A total 3% of the teams achieved successful results and were more likely to have a paramedic as the ALS provider (p = 0.028). A sensitivity analysis excluding physicians was conducted and showed that high-performance teams had significantly higher skill assessments for primary survey (p = 0.004), injury recognition (p = 0.002), exposure (p = 0.006), adherence to clinical practice guidelines (p = 0.032), and medical device use (p = 0.002).

CONCLUSION
Our study found that ALS provider is associated with overall simulation performance in prehospital ALS teams, with military paramedics more likely to be successful. These findings have implications for the training and staffing of prehospital ALS teams, suggesting that teams should be composed accordingly and that training should focus on skills affected by the ALS provider type.

LEVEL OF EVIDENCE
Prognostic and Epidemiological; Level IV.
Cardiomyocyte electrophysiology and its modulation: current views and future prospects
Authors: Huang Christopher L.-H. , Lei Ming 
Published: May 2023

Normal and abnormal cardiac rhythms are of key physiological and clinical interest. This introductory article begins from Sylvio Weidmann's key historic 1950s microelectrode measurements of cardiac electrophysiological activity and Singh & Vaughan Williams's classification of cardiotropic targets. It then proceeds to introduce the insights into cardiomyocyte function and its regulation that subsequently emerged and their therapeutic implications. We recapitulate the resulting view that surface membrane electrophysiological events underlying cardiac excitation and its initiation, conduction and recovery constitute the final common path for the cellular mechanisms that impinge upon this normal or abnormal cardiac electrophysiological activity. We then consider progress in the more recently characterized successive regulatory hierarchies involving Ca2+homeostasis, excitation–contraction coupling and autonomic G-protein signalling and their often reciprocal interactions with the surface membrane events, and their circadian rhythms. Then follow accounts of longer-term upstream modulation processes involving altered channel expression, cardiomyocyte energetics and hypertrophic and fibrotic cardiac remodelling. Consideration of these developments introduces each of the articles in thisPhil. Trans. Btheme issue. The findings contained in these articles translate naturally into recent classifications of cardiac electrophysiological targets and drug actions, thereby encouraging future iterations of experimental cardiac electrophysiological discovery, and testing directed towards clinical management.This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.
Compartmentalized cAMP signalling and control of cardiac rhythm
Authors: Tomek Jakub , Zaccolo Manuela 
Published: May 2023

In the last 30 years, the field of cyclic adenosine 3′,5′-monophosphate (cAMP) signalling has witnessed a transformative development with the realization that cAMP is compartmentalized and that spatial regulation of cAMP is critical for faithful signal propagation and hormonal specificity. This recognition has changed our understanding of cAMP signalling from the canonical model, where a linear pathway connects a plasma membrane receptor to intracellular effectors and their targets, to a model where signal transduction occurs within a complex network of alternative branches and where an individual receptor leads to activation of a limited fraction of the network, enabled by local regulation of independent signalling units, resulting in a specific functional outcome. The cardiac myocyte has served as the cell model for many of the original findings leading to this paradigm. In this review, we cover some of the evidence supporting this new perspective and discuss how this model is providing novel mechanistic insight into cardiac myocyte physiology. With a focus on the regulation of cardiac rhythm, we consider how this model can provide an original framework for the identification of disease mechanisms.
This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.
Human induced pluripotent stem cell-derived cardiac myocytes and sympathetic neurons in disease modelling
Authors: Li Ni , Edel Michael , Liu Kun , Denning Chris , Betts Jacob , Neely Oliver C. , Li Dan , Paterson David J. 
Published: May 2023

Human induced pluripotent stem cells (hiPSC) offer an unprecedented opportunity to generate model systems that facilitate a mechanistic understanding of human disease. Current differentiation protocols are capable of generating cardiac myocytes (hiPSC-CM) and sympathetic neurons (hiPSC-SN). However, the ability of hiPSC-derived neurocardiac co-culture systems to replicate the human phenotype in disease modelling is still in its infancy. Here, we adapted current methods for efficient and replicable induction of hiPSC-CM and hiPSC-SN. Expression of cell-type-specific proteins were confirmed by flow cytometry and immunofluorescence staining. The utility of healthy hiPSC-CM was tested with pressor agents to develop a model of cardiac hypertrophy. Treatment with angiotensin II (AngII) resulted in: (i) cell and nuclear enlargement, (ii) enhanced fetal gene expression, and (iii) FRET-activated cAMP responses to adrenergic stimulation. AngII or KCl increased intracellular calcium transients in hiPSC-SN. Immunostaining in neurocardiac co-cultures demonstrated anatomical innervation to myocytes, where myocyte cytosolic cAMP responses were enhanced by forskolin compared with monocultures. In conclusion, human iPSC-derived cardiac myocytes and sympathetic neurons replicated many features of the anatomy and (patho)physiology of these cells, where co-culture preparations behaved in a manner that mimicked key physiological responses seen in other mammalian systems.
This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.
Generation of cardiomyocytes from human-induced pluripotent stem cells resembling atrial cells with ability to respond to adrenoceptor agonists
Authors: Ahmad Faizzan S. , Jin Yongcheng , Grassam-Rowe Alexander , Zhou Yafei , Yuan Meng , Fan Xuehui , Zhou Rui , Mu-u-min Razik , O'Shea Christopher , Ibrahim Ayman M. , Hyder Wajiha , Aguib Yasmine , Yacoub Magdi , Pavlovic Davor , Zhang Yanmin , Tan Xiaoqiu , Lei Ming , Terrar Derek A. 
Published: May 2023

Atrial fibrillation (AF) is the most common chronic arrhythmia presenting a heavy disease burden. We report a new approach for generating cardiomyocytes (CMs) resembling atrial cells from human-induced pluripotent stem cells (hiPSCs) using a combination of Gremlin 2 and retinoic acid treatment. More than 40% of myocytes showed rod-shaped morphology, expression of CM proteins (including ryanodine receptor 2,
α
-actinin-2 and F-actin) and striated appearance, all of which were broadly similar to the characteristics of adult atrial myocytes (AMs). Isolated myocytes were electrically quiescent until stimulated to fire action potentials with an AM profile and an amplitude of approximately 100 mV, arising from a resting potential of approximately −70 mV. Single-cell RNA sequence analysis showed a high level of expression of several atrial-specific transcripts including
NPPA
,
MYL7
,
HOXA3
,
SLN
,
KCNJ4
,
KCNJ5
and
KCNA5
. Amplitudes of calcium transients recorded from spontaneously beating cultures were increased by the stimulation of
α
-adrenoceptors (activated by phenylephrine and blocked by prazosin) or
β
-adrenoceptors (activated by isoproterenol and blocked by CGP20712A). Our new approach provides human AMs with mature characteristics from hiPSCs which will facilitate drug discovery by enabling the study of human atrial cell signalling pathways and AF.

This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.
Learning to Adapt - Deep Reinforcement Learning in Treatment-Resistant Prostate Cancer
Authors: Gallagher Kit , Strobl Maximillian , Gatenby Robert , Maini Philip , Anderson Alexander 
Published: May 2023

AbstractStandard-of-care treatment regimes have long been designed to for maximal cell kill, yet these strategies often fail when applied to treatment–resistant tumors, resulting in patient relapse. Adaptive treatment strategies have been developed as an alternative approach, harnessing intra-tumoral competition to suppress the growth of treatment resistant populations, to delay or even prevent tumor progression. Following recent clinical implementations of adaptive therapy, it is of significant interest to optimise adaptive treatment protocols. We propose the application of deep reinforcement learning models to provide generalised solutions within adaptive drug scheduling, and demonstrate this framework can outperform the current adaptive protocols, extending time to progression by up to a quarter. This strategy is robust to varying model parameterisations, and the underlying tumor model. We demonstrate the deep learning framework can produce interpretable, adaptive strategies based on a single tumor burden threshold, replicating and informing a novel, analytically–derived optimal treatment strategy with no knowledge of the underlying mathematical tumor model. This approach is highly relevant beyond the simple, analytically–tractable tumor model considered here, demonstrating the capability of deep learning frameworks to help inform and develop treatment strategies in complex settings. Finally, we propose a pathway to integrate mechanistic modelling with DRL to tailor generalist treatment strategies to individual patients in the clinic, generating personalised treatment schedules that consistently outperform clinical standard-of-care protocols.
Food web complexity modulates environmental impacts on food chain length
Authors: Shibasaki Shota , Terui Akira 
Published: May 2023

AbstractFood chain length (FCL), a crucial aspect of biodiversity, has long been debated for its determinants. Previous studies proposed resource availability, disturbance, and ecosystem size as environmental drivers. However, studies using stable isotope approaches have shown inconsistent results, indicating missing links between environmental drivers and FCL. Here, we hypothesized that species richness and motifs (i.e., 3-species subgraphs) modulated environmental effects on FCL. Combining empirical food webs with ourN-species food web model, we found that FCL disproportionately changed at low species richness with saturation at high species richness. This functional response was essential to the interdependent effects of disturbance and ecosystem size in our model. Disturbance more strongly regulated FCL in smaller ecosystems, where species richness was low. Similarly, increasing ecosystem size enhanced FCL under strong, but not weak, disturbance regimes. Our study suggests that internal food web structure should deepen our understanding of how FCL changes over environments.
Ant impacts on global patterns of bird elevational diversity
Authors: Srinivasan Umesh , Shanker Kartik , Price Trevor D. 
Published: May 2023

AbstractAcross the world’s mountains, elevation-species richness relationships are highly variable. Here, using data on bird species elevational distributions from all 46 of the world’s major mountain ranges, bird species dietary traits, and the distribution of the low-elevation ant genusOecophylla, we show that global patterns in bird elevational diversity are likely to be affected by competition with ants.Oecophyllais an exceptionally abundant and aggressive predator of invertebrates, which preys on the same species that sympatric invertivorous bird species feed on. In mountain ranges withOecophyllapresent in the foothills, maximum species richness of invertivorous birds occurs, on average, at 960m, ∼450m higher than in mountain ranges withoutOecophylla. Further, in mountain ranges withOecophylla, species richness of invertivorous birds increases initially with with elevation to produce a mid-elevation peak in invertivore bird species richness. WhereOecophyllais absent, invertivore bird species richness generally shows monotonic declines with increasing elevation. We attribute the pattern to the following mechanism: first,Oecophyllareduces prey density for invertivorous birds; second, low invertebrate prey abundance reduces invertivorous bird density and third, lower bird density is correlated with lower bird species richness. Because invertivores dominate montane bird communities, global elevational bird diversity patterns are also driven byOecophylla. The findings emphasize how competitive interactions between distantly related taxa set geographical range limits.
scGPT: Towards Building a Foundation Model for Single-Cell Multi-omics Using Generative AI
Authors: Cui Haotian , Wang Chloe , Maan Hassaan , Pang Kuan , Luo Fengning , Wang Bo 
Published: May 2023

AbstractGenerative pre-trained models have achieved remarkable success in various domains such as natural language processing and computer vision. Specifically, the combination of large-scale diverse datasets and pre-trained transformers has emerged as a promising approach for developing foundation models. Drawing parallels between linguistic constructs and cellular biology — where texts comprise words, similarly, cells are defined by genes — our study probes the applicability of foundation models to advance cellular biology and genetics research. Utilizing the burgeoning single-cell sequencing data, we have pioneered the construction of a foundation model for single-cell biology, scGPT, which is based on generative pre-trained transformer across a repository of over 33 million cells. Our findings illustrate that scGPT, a generative pre-trained transformer, effectively distills critical biological insights concerning genes and cells. Through the further adaptation of transfer learning, scGPT can be optimized to achieve superior performance across diverse downstream applications. This includes tasks such as cell-type annotation, multi-batch integration, multi-omic integration, genetic perturbation prediction, and gene network inference. The scGPT codebase is publicly available athttps://github.com/bowang-lab/scGPT.
Collective cell migration due to guidance-by-followers is robust to multiple stimuli
Authors: Müller Robert , Boutillon Arthur , Jahn Diego , Starruß Jörn , David Nicolas B. , Brusch Lutz 
Published: May 2023

AbstractCollective cell migration is an important process during biological development and tissue repair, but may turn malignant during tumor invasion. Mathematical and computational models are essential to unravel the mechanisms of self-organization that underlie the emergence of collective migration from the interactions among individual cells. Recently, guidance-by-followers was identified as one such underlying mechanism of collective cell migration in the zebrafish embryo. This poses the question how guidance stimuli are integrated when multiple cells interact simultaneously. Here, we extend a recent individual-based model by an integration step of the vectorial guidance stimuli and compare model predictions obtained for various variants of the mechanism (arithmetic mean of stimuli, dominance of stimulus with largest transmission interface, dominance of most head-on stimulus). Simulations are carried out and quantified within the modeling and simulation framework Morpheus. Collective cell migration is sfound to be robust and qualitatively identical for all considered variants of stimulus integration. Moreover, this study highlights the role of individual-based modeling approaches for understanding collective phenomena at the population scale that emerge from cell-cell interactions.
Anaplastic Thyroid Cancer Cells Upregulate Mitochondrial One-Carbon Metabolism To Meet Purine Demand, Eliciting A Critical Targetable Vulnerability
Authors: Sugarman Adam J. , Huynh Luong Do , Shabro Aidin , Di Cristofano Antonio 
Published: May 2023

AbstractAnaplastic thyroid cancer (ATC) is one of the most aggressive and lethal tumor types, characterized by loss of differentiation, epithelial-to-mesenchymal transition, extremely high proliferation rate, and generalized resistance to therapy. To identify novel relevant, targetable molecular alterations, we analyzed gene expression profiles from a genetically engineered ATC mouse model and from human patient datasets, and found consistent upregulation of genes encoding enzymes involved in the one-carbon metabolic pathway, which uses serine and folates to generate both nucleotides and glycine.Genetic and pharmacological inhibition ofSHMT2, a key enzyme of the mitochondrial arm of the one-carbon pathway, rendered ATC cells glycine auxotroph and led to significant inhibition of cell proliferation and colony forming ability, which was primarily caused by depletion of the purine pool. Notably, these growth-suppressive effects were significantly amplified when cells were grown in the presence of physiological types and levels of folates. Genetic depletion ofSHMT2dramatically impaired tumor growth in vivo, both in xenograft models and in an immunocompetent allograft model of ATC.Together, these data establish the upregulation of the one-carbon metabolic pathway as a novel and targetable vulnerability of ATC cells, which can be exploited for therapeutic purposes.