bluuebunny/crossref_metadata_2025_split huggingface dataset:
Body Composition and Radiomics From 18F-FDG PET/CT Together Help Predict Prognosis for Patients With Stage IV Non–Small Cell Lung Cancer
Authors: Zhang Yi , Tan Weiyue , Zheng Zhonghang , Wang Jie , Xing Ligang , Sun Xiaorong 
Published: November 2023

Purpose
To determine whether integration of data on body composition and radiomic features obtained using baseline 18F-FDG positron emission tomography/computed tomography (PET/CT) images can be used to predict the prognosis of patients with stage IV non–small cell lung cancer (NSCLC).

Methods
A total of 107 patients with stage IV NSCLC were retrospectively enrolled in this study. We used the 3D Slicer (The National Institutes of Health, Bethesda, Maryland) software to extract the features of PET and CT images. Body composition measurements were taken at the L3 level using the Fiji (Curtis Rueden, Laboratory for Optical and Computational Instrumentation, University of Wisconsin, Madison) software. Independent prognostic factors were defined by performing univariate and multivariate analyses for clinical factors, body composition features, and metabolic parameters. Data on body composition and radiomic features were used to build body composition, radiomics, and integrated (combination of body composition and radiomic features) nomograms. The models were evaluated to determine their prognostic prediction capabilities, calibration, discriminatory abilities, and clinical applicability.

Results
Eight radiomic features relevant to progression-free survival (PFS) were selected. Multivariate analysis showed that the visceral fat area/subcutaneous fat area ratio independently predicted PFS (P = 0.040). Using the data for body composition, radiomic features, and integrated features, nomograms were established for the training (areas under the curve = 0.647, 0.736, and 0.803, respectively) and the validation sets (areas under the receiver operating characteristic = 0.625, 0.723, and 0.866, respectively); the integrated model showed better prediction ability than that of the other 2 models. The calibration curves revealed that the integrated nomogram exhibited a better agreement between the estimation and the actual observation in terms of prediction of the probability of PFS than that of the other 2 models. Decision curve analysis revealed that the integrated nomogram was superior to the body composition and radiomics nomograms for predicting clinical benefit.

Conclusion
Integration of data on body composition and PET/CT radiomic features can help in prediction of outcomes in patients with stage IV NSCLC.
Machine Learning–based Prediction of Postoperative Pancreatic Fistula Following Pancreaticoduodenectomy
Authors: Verma Arjun , Balian Jeffrey , Hadaya Joseph , Premji Alykhan , Shimizu Takayuki , Donahue Timothy , Benharash Peyman 
Published: November 2023

Objective:
The aim of this study was to develop a novel machine learning model to predict clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreaticoduodenectomy (PD).

Background:
Accurate prognostication of CR-POPF may allow for risk stratification and adaptive treatment strategies for potential PD candidates. However, antecedent models, such as the modified Fistula Risk Score (mFRS), are limited by poor discrimination and calibration.

Methods:
All records entailing PD within the 2014 to 2018 American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) were identified. In addition, patients undergoing PD at our institution between 2013 and 2021 were queried from our local data repository. An eXtreme Gradient Boosting (XGBoost) model was developed to estimate the risk of CR-POPF using data from the ACS NSQIP and evaluated using institutional data. Model discrimination was estimated using the area under the receiver operating characteristic (AUROC) and area under the precision recall curve (AUPRC).

Results:
Overall, 12,281 and 445 patients undergoing PD were identified within the 2014 to 2018 ACS NSQIP and our institutional registry, respectively. Application of the XGBoost and mFRS scores to the internal validation dataset revealed that the former model had significantly greater AUROC (0.72 vs 0.68, P<0.001) and AUPRC (0.22 vs 0.18, P<0.001). Within the external validation dataset, the XGBoost model remained superior to the mFRS with an AUROC of 0.79 (95% CI: 0.74–0.84) versus 0.75 (95% CI: 0.70–0.80, P<0.001). In addition, AUPRC was higher for the XGBoost model, compared with the mFRS.

Conclusion:
Our novel machine learning model consistently outperformed the previously validated mFRS within internal and external validation cohorts, thereby demonstrating its generalizability and utility for enhancing prediction of CR-POPF.
MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors
Authors: Kim HaEun , Lebeau Benjamin , Papadopoli David , Jovanovic Predrag , Russo Mariana , Avizonis Daina , Morita Masahiro , Afzali Farzaneh , Ursini-Siegel Josie , Postovit Lynne-Marie , Witcher Michael , Topisirovic Ivan 
Published: November 2023

SummaryEmerging data suggest a significant cross-talk between metabolic and epigenetic programs. However, the relationship between the mechanistic target of rapamycin (mTOR) which is a pivotal regulator of cellular metabolism, and epigenetic modifications remains poorly understood. We thus explored the impact of modulating mTOR signaling on histone methylation, a well-known epigenetic modification. Our results showed that mTORC1 activation caused by abrogation of TSC2 increased H3K27me3 but not H3K4me3 or H3K9me3. This appeared to be mediated via the induction of EZH2 protein synthesis, downstream of 4EBPs. Surprisingly, mTOR inhibition also induced H3K27me3 independently of TSC2. This coincided with reduced EZH2 and increased EZH1 protein levels. Notably, the ability of mTOR inhibitors to induce H3K27me3 levels was positively correlated with their anti-proliferative effects. Collectively, our findings demonstrate that both activation and inhibition of mTOR selectively increase H3K27me3 by distinct mechanisms, whereby the ability of mTOR inhibitors to induce H3K27me3 influences their anti-proliferative effects.HighlightsParadoxically, both mTOR activation and inhibition induce H3K27me3.The effect of mTOR inhibitors on H3K27me3 are not secondary to cell cycle arrest.H3K27me3 triggered by mTOR suppression coincides with perturbations in EZH1/2 ratio.H3K27me3 impacts on the anti-proliferative effects of mTOR inhibitors.
Emergence and spread of feline infectious peritonitis due to a highly pathogenic canine/feline recombinant coronavirus
Authors: Attipa Charalampos , Warr Amanda S , Epaminondas Demetris , O’Shea Marie , Hanton Andrew J , Fletcher Sarah , Malbon Alexandra , Lyraki Maria , Hammond Rachael , Hardas Alexandros , Zanti Antria , Loukaidou Stavroula , Gentil Michaela , Gunn-Moore Danielle , Mazeri Stella , Tait-Burkard Christine 
Published: November 2023

AbstractCross-species transmission of coronaviruses (CoVs) poses a serious threat to both animal and human health1–3. Whilst the large RNA genome of CoVs shows relatively low mutation rates, recombination within genera is frequently observed and demonstrated4–7. Companion animals are often overlooked in the transmission cycle of viral diseases; however, the close relationship of feline (FCoV) and canine CoV (CCoV) to human hCoV-229E5,8, as well as their susceptibility to SARS-CoV-29highlight their importance in potential transmission cycles. Whilst recombination between CCoV and FCoV of a large fragment spanning orf1b to M has been previously described5,10, here we report the emergence of a novel, highly pathogenic FCoV-CCoV recombinant responsible for a rapidly spreading outbreak of feline infectious peritonitis (FIP), originating in Cyprus11. The minor recombinant region, spanning spike (S), shows 96.5% sequence identity to the pantropic canine coronavirus NA/09. Infection has rapidly spread, infecting cats of all ages. Development of FIP appears very frequent and sequence identities of samples from cats in different districts of the island is strongly supportive of direct transmission. A near cat-specific deletion in the domain 0 of S is present in >90% of FIP cats. It is unclear as yet whether this deletion is directly associated with disease development and may be linked to a biotype switch12. The domain 0 deletion and several amino acid changes in S, particularly the receptor binding domain, indicate potential changes to receptor binding and cell tropism.
The effect of temperature on the boundary conditions of West Nile virus circulation in Europe
Authors: de Freitas Eduardo Costa , Streng Kiki , de Souza Santos Mariana Avelino , Counotte Michel Jacques 
Published: November 2023

AbstractWest Nile virus (WNV) is a vector-borne flavivirus that causes an increasing number of human and equine West Nile fever cases in Europe. While the virus has been present in the Mediterranean basin and the Balkans since the 1960s, recent years have witnessed its northward expansion, with the first human cases reported in Germany in 2018 and the Netherlands in 2020. WNV transmission and amplification within mosquitoes are temperature-dependent. This study applies a mathematical modelling approach to assess the conditions under which WNV circulation occurs based on the proportion of mosquitoes’ bites on WNV-competent birds (dilution), vector-host ratios, mosquito season length and the observed daily temperature data in five distinct European regions where previous WNV circulation has been observed within the Netherlands, Germany, Spain, Italy, and Greece. We observed that the number of days in which the basic reproduction number (R0) is above one, increased over the last 40 years in all five regions. In the Netherlands, the number of days in which the R0is above one, is 70% lower than in Spain. The temperature in Greece, Spain and Italy allowed for circulation under low vector-host ratios, and at a high dilution. On the other hand in the Netherlands and Germany, given the observed daily temperature, the thresholds for circulation requires a lower dilution and higher vector-host ratios. For the Netherlands, a short window of introductions between late May and mid-June would result in detectable outbreaks. Our findings revealed that the temperate maritime climate of the Netherlands allows WNV circulation primarily during warmer summers, and only under high vector-host ratios. This research contributes valuable insights into the dynamic relationship between temperature, vector properties, and WNV transmission, offering guidance for proactive strategies in addressing this emerging health threat in Europe.
Neural network extrapolation to distant regions of the protein fitness landscape
Authors: Fahlberg Sarah A , Freschlin Chase R , Heinzelman Pete , Romero Philip A 
Published: November 2023

AbstractMachine learning (ML) has transformed protein engineering by constructing models of the underlying sequence-function landscape to accelerate the discovery of new biomolecules. ML-guided protein design requires models, trained on local sequence-function information, to accurately predict distant fitness peaks. In this work, we evaluate neural networks’ capacity to extrapolate beyond their training data. We perform model-guided design using a panel of neural network architectures trained on protein G (GB1)-Immunoglobulin G (IgG) binding data and experimentally test thousands of GB1 designs to systematically evaluate the models’ extrapolation. We find each model architecture infers markedly different landscapes from the same data, which give rise to unique design preferences. We find simpler models excel in local extrapolation to design high fitness proteins, while more sophisticated convolutional models can venture deep into sequence space to design proteins that fold but are no longer functional. Our findings highlight how each architecture’s inductive biases prime them to learn different aspects of the protein fitness landscape.
Discovery of the sEH Inhibitor Epoxykynin as Potent Kynurenine Pathway Modulator
Authors: Dötsch Lara , Davies Caitlin , Hennes Elisabeth , Schönfeld Julia , Kumar Adarsh , Da Cruz Lopes Guita Celine , Ehrler Johanna H.M. , Hiesinger Kerstin , Thavam Sasikala , Janning Petra , Sievers Sonja , Knapp Stefan , Proschak Ewgenij , Ziegler Slava , Waldmann Herbert 
Published: November 2023

AbstractDisease-related phenotypic assays enable unbiased discovery of novel bioactive small molecules and may provide novel insights into physiological systems and unprecedented molecular modes-of-action (MMOA). Herein we report the identification and characterization of epoxykynin, a potent inhibitor of the soluble epoxide hydrolase (sEH). Epoxykynin was discovered by means of a cellular assay monitoring modulation of kynurenine (Kyn) levels in BxPC-3 cells upon stimulation with the cytokine interferon-γ (IFN-γ) and subsequent target identification employing affinity-based chemical proteomics. Increased Kyn levels are associated with immune suppression in the tumor microenvironment and, thus, the Kyn pathway and its key player indoleamine 2,3-dioxygenase 1 (IDO1) are appealing targets in immuno-oncology. However, targeting IDO1 directly has led to limited success in clinical investigations, demonstrating that alternative approaches to reduce Kyn levels are in high demand. We uncover a cross-talk between sEH and the Kyn pathway that may provide new opportunities to revert cancer-induced immune tolerance.
Short internal open reading frames regulate the translation of N-terminally truncated proteoforms
Authors: Fettig Raphael , Gonda Zita , Walter Niklas , Sallmann Paul , Thanisch Christiane , Winter Markus , Bauer Susanne , Zhang Lei , Linden Greta , Litfin Margarethe , Etard Christelle , Armant Olivier , Vázquez Olalla , Kassel Olivier 
Published: November 2023

AbstractInternal translation initiation sites, as revealed by ribosome profiling experiments can potentially drive the translation of many N-terminally truncated proteoforms. We have identified an mRNA cis-regulatory element which regulates their translation. nTRIP6 represents a short nuclear proteoform of the cytoplasmic protein TRIP6. We have previously reported that nTRIP6 regulates the dynamics of skeletal muscle progenitor differentiation. Here we show that nTRIP6 is generated by translation initiation at an internal AUG. Its translation is repressed by an internal short open reading frame (sORF) immediately upstream of the nTRIP6 AUG. Consistent with this representing a more general regulatory feature, we have identified other N-terminally truncated proteoforms which are repressed by internal sORFs. In anin vitromodel of myogenic differentiation, the translation of nTRIP6 is transiently de-repressed in a mechanistic Target of Rapamycin Complex 1-dependent manner. Thus, the translation of N-terminally truncated proteoforms can be regulated independently of the canonical ORF.
Structure and position-specific interactions of prion-like domains in transcription factor Efg1 phase separation
Authors: Wang Szu-Huan , Zheng Tongyin , Fawzi Nicolas L. 
Published: November 2023

AbstractCandida albicans, a prominent member of the human microbiome, can make an opportunistic switch from commensal coexistence to pathogenicity accompanied by an epigenetic shift between the white and opaque cell states. This transcriptional switch is under precise regulation by a set of transcription factors (TFs), with Enhanced Filamentous Growth Protein 1 (Efg1) playing a central role. Previous research has emphasized the importance of Egf1’s prion-like domain (PrLD) and the protein’s ability to undergo phase separation for the white-to-opaque transition ofC. albicans. However, the underlying molecular mechanisms of Efg1 phase separation have remained underexplored. In this study, we delved into the biophysical basis of Efg1 phase separation, revealing the significant contribution of both N-terminal (N) and C-terminal (C) PrLDs. Through NMR structural analysis, we found that Efg1 N-PrLD and C-PrLD are mostly disordered though have prominent partial α-helical secondary structures in both domains. NMR titration experiments suggest that the partially helical structures in N-PrLD act as hubs for self-interaction as well as Efg1 interaction with RNA. Using condensed-phase NMR spectroscopy, we uncovered diverse amino acid interactions underlying Efg1 phase separation. Particularly, we highlight the indispensable role of tyrosine residues within the transient α-helical structures of PrLDs particularly in the N-PrLD compared to the C-PrLD in stabilizing phase separation. Our study provides evidence that the transient α-helical structure is present in the phase separated state and highlights the particular importance of aromatic residues within these structures for phase separation. Together, these results enhance the understanding ofC. albicansTF interactions that lead to virulence and provide a crucial foundation for potential antifungal therapies targeting the transcriptional switch.Statement of SignificancePhase separated condensates have been found across the domains of life and many types of cells. To understand their varied functions, seeing the residue-by-residue details of the structure and interactions of component protein constituents is essential. A set of transcription factors that phase-separate controls cell fate of the pathogenic yeast Candida albicans. Here, we examine the structural and interaction details of a main regulator of this process, Efg1, using NMR spectroscopy and biochemical assays. We find Efg1’s phase-separating domains are not entirely disordered as often assumed but in fact contain helical regions that persist upon phase separation. We also reveal the balance of contacts formed in the condensed phase and the importance of specific residues and regions in phase separation.
A negative feedback loop is critical for recovery of RpoS after stress inEscherichia coli
Authors: Bouillet Sophie , Hamdallah Issam , Majdalani Nadim , Tripathi Arti , Gottesman Susan 
Published: November 2023

AbstractRpoS is an alternative sigma factor needed for the induction of the general stress response in many gammaproteobacteria. Tight regulation of RpoS levels and activity is required for bacterial growth and survival under stress. InEscherichia coli, various stresses lead to higher levels of RpoS due to increased translation and decreased degradation. During non-stress conditions, RpoS is unstable, because the adaptor protein RssB delivers RpoS to the ClpXP protease. RpoS degradation is prevented during stress by the sequestration of RssB by anti-adaptors, each of which is induced in response to specific stresses. Here, we examined how the stabilization of RpoS is reversed during recovery of the cell from stress. We found that RpoS degradation quickly resumes after recovery from phosphate starvation, carbon starvation, and when transitioning from stationary phase back to exponential phase. This process is in part mediated by the anti-adaptor IraP, known to promote RpoS stabilization during phosphate starvation via the sequestration of adaptor RssB. The rapid recovery from phosphate starvation is dependent upon a feedback loop in which RpoS transcription ofrssB, encoding the adaptor protein, plays a critical role. Crl, an activator of RpoS that specifically binds to and stabilizes the complex between the RNA polymerase and RpoS, is also required for the feedback loop to function efficiently, highlighting a critical role for Crl in restoring RpoS basal levels.Author summaryIn their native environments, bacteria are exposed to constant changes in nutrient availability, as well as other biotic and abiotic stressors. To adjust to these changes, bacteria must rewire gene expression to adapt to or avoid stress-induced damage. A key player in the global response to general stresses is the alternative sigma factor RpoS, a promoter-specificity determining subunit of RNA polymerase. RpoS levels increase with stress, due to increased translation and stabilization of the otherwise unstable RpoS protein. Here, we examine how the cell restores homeostasis after the stress has passed. We show that a negative feedback loop in which RpoS regulates the transcription of an adaptor for proteolysis poises the cell to rapidly resume RpoS degradation upon the exit from stress.
Key morphological features of human pyramidal neurons
Authors: Benavides-Piccione Ruth , Blazquez-Llorca  , Kastanauskaite Asta , Fernaud Isabel , Gonzalez-Tapia Silvia , DeFelipe Javier 
Published: November 2023

AbstractThe basic building block of the cerebral cortex, the pyramidal cell, has been shown to be characterized by a markedly different dendritic structure among layers, cortical areas, and species. Functionally, differences in the structure of their dendrites and axons are critical in determining how neurons integrate information. However, within the human cortex, these neurons have not been quantified in detail. In the present work, we performed intracellular injections of Lucifer Yellow and 3D reconstructed over 200 pyramidal neurons, including apical and basal dendritic and local axonal arbors and dendritic spines, from human occipital primary visual area and associative temporal cortex. We found that human pyramidal neurons from temporal cortex were larger, displayed more complex apical and basal structural organization and had more spines compared to those in primary sensory cortex. Moreover, these human neocortical neurons displayed specific shared and distinct characteristics in comparison to previously published human hippocampal pyramidal neurons. Additionally, we identified distinct morphological features in human neurons that set them apart from mouse neurons. Lastly, we observed certain consistent organizational patterns shared across species. This study emphasizes the existing diversity within pyramidal cell structures across different cortical areas and species, suggesting substantial species-specific variations in their computational properties.