bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep learning in integrating spatial transcriptomics with other modalities
Authors: Luo Jiajian , Fu Jiye , Lu Zuhong , Tu Jing 
Published: January 2025

Abstract
Spatial transcriptomics technologies have been extensively applied in biological research, enabling the study of transcriptome while preserving the spatial context of tissues. Paired with spatial transcriptomics data, platforms often provide histology and (or) chromatin images, which capture cellular morphology and chromatin organization. Additionally, single-cell RNA sequencing (scRNA-seq) data from matching tissues often accompany spatial data, offering a transcriptome-wide gene expression profile of individual cells. Integrating such additional data from other modalities can effectively enhance spatial transcriptomics data, and, conversely, spatial transcriptomics data can supplement scRNA-seq with spatial information. Moreover, the rapid development of spatial multi-omics technology has spurred the demand for the integration of spatial multi-omics data to present a more detailed molecular landscape within tissues. Numerous deep learning (DL) methods have been developed for integrating spatial transcriptomics with other modalities. However, a comprehensive review of DL approaches for integrating spatial transcriptomics data with other modalities remains absent. In this study, we systematically review the applications of DL in integrating spatial transcriptomics data with other modalities. We first delineate the DL techniques applied in this integration and the key tasks involved. Next, we detail these methods and categorize them based on integrated modality and key task. Furthermore, we summarize the integration strategies of these integration methods. Finally, we discuss the challenges and future directions in integrating spatial transcriptomics with other modalities, aiming to facilitate the development of robust computational methods that more comprehensively exploit multimodal information.
TRIAGE: an R package for regulatory gene analysis
Authors: Zhao Qiongyi , Shim Woo Jun , Sun Yuliangzi , Sinniah Enakshi , Shen Sophie , Boden Mikael , Palpant Nathan J 
Published: January 2025

Abstract
Regulatory genes are critical determinants of cellular responses in development and disease, but standard RNA sequencing (RNA-seq) analysis workflows, such as differential expression analysis, have significant limitations in revealing the regulatory basis of cell identity and function. To address this challenge, we present the TRIAGE R package, a toolkit specifically designed to analyze regulatory elements in both bulk and single-cell RNA-seq datasets. The package is built upon TRIAGE methods, which leverage consortium-level H3K27me3 data to enrich for cell-type-specific regulatory regions. It facilitates the construction of efficient and adaptable pipelines for transcriptomic data analysis and visualization, with a focus on revealing regulatory gene networks. We demonstrate the utility of the TRIAGE R package using three independent transcriptomic datasets, showcasing its integration into standard analysis workflows for examining regulatory mechanisms across diverse biological contexts. The TRIAGE R package is available on GitHub at https://github.com/palpant-comp/TRIAGE_R_Package.
FlexLMM: a Nextflow linear mixed model framework for GWAS
Authors: Pierotti Saul , Fitzgerald Tomas , Birney Ewan 
Published: January 2025

Abstract

Summary
Linear mixed models (LMMs) are a commonly used statistical approach in genome-wide association studies when population structure is present. However, naive permutations of the phenotype to empirically estimate the null distribution of a statistic of interest are not appropriate in the presence of population structure or covariates. This is because the samples are not exchangeable with each other under the null hypothesis, and because permuting the phenotypes breaks the relationship among those and eventual covariates. For this reason, we developed FlexLMM, a Nextflow pipeline that can perform appropriate permutations in LMMs while allowing for flexibility in the definition of the exact statistical model to be used. FlexLMM can set a significance threshold via permutations, thanks to a two-step process where the population structure is first regressed out, and only then are the permutations performed on the uncorrelated residuals. We envision this pipeline will be particularly useful for researchers working on multi-parental crosses among inbred lines of model organisms or farm animals and plants.

Availability and implementation
The source code and documentation for the FlexLMM is available at https://github.com/birneylab/flexlmm.
Mechanistic target of rapamycin signaling activity in the human placenta across gestation and in maternal obesity
Authors: Bidne Katie L , Erickson Kathryn E , Powell Theresa L , Jansson Thomas 
Published: January 2025

Abstract
The mechanistic target of rapamycin system is vital to placental development, formation, and function. Alterations in this system in the placenta have been associated with altered fetal growth. However, changes in placental mechanistic target of rapamycin signaling across gestation are poorly understood. We collected 81 human placental samples from 4 to 40 weeks gestation to test the hypothesis that placental mechanistic target of rapamycin signaling activity increases over gestation and is activated in maternal obesity in early gestation. Proteins involved in upstream mechanistic target of rapamycin regulation and mTORC1/2 downstream signaling were quantified using immunoblotting in placentas of male or female fetuses. Readouts of mTORC1 activation, phospho-rpS6, and phospho-4EBP1 were highest in first trimester and decreased across gestation. Phosphorylation of AKT (308 and 473) increased over gestation. Interestingly, abundance of cytochrome c oxidase I and mitochondrial ATP synthase, key subunits of mitochondrial complexes III/IV and V, respectively, were elevated in first trimester obese placentas compared to control, but only in placenta from female fetuses. We suggest that the high placental mechanistic target of rapamycin signaling activity in early pregnancy may be related to the high anabolism and active trophoblast proliferation and invasion in the second half of the first trimester. In addition, we conclude that maternal obesity has only limited impact on this key placental signaling pathway across gestation in women.
MRI versus relapse: optimal activity monitoring for management of progressive multiple sclerosis
Authors: Giovannoni Gavin , Hetherington Suzannah , Jones Eddie , Dominguez Castro Patricia , Karu Himanshu , Ansari Soudeh , Karlsson Goeril , de las Heras Virginia , Lines Carol 
Published: January 2025

Abstract
Secondary progressive multiple sclerosis is often categorized as ‘active’/‘non-active’ based on inflammatory activity on MRI, or relapse; however, the value of MRI/relapse as indicators of disease activity in real-world and clinical trial settings merits further investigation. We separately analysed retrospective data from patients with clinically diagnosed secondary progressive multiple sclerosis in the Adelphi Real-World Disease Specific Programme (a cross-sectional survey) in multiple sclerosis (Adelphi: n = 2554) and the placebo group of the Phase III EXploring the efficacy and safety of siponimod in PAtients with secoNDary progressive multiple sclerosis (EXPAND) trial, [EXPAND-PBO (placebo group of the EXPAND): n = 546] to assess: differences between active/non-active disease in the real-world (characteristics; monitoring); the value of MRI and relapse to indicate disease activity; and the number and characteristics of non-active patients with disease activity in the clinical study. In Adelphi, 1889 patients had ‘active’ disease (≥1 relapse in the year before index date and/or ≥1 new lesion on most recent MRI) versus 665 with ‘non-active’ disease (no relapses in the previous year and no new lesions on MRI); median age was 48 versus 53 years; 73.5 versus 87.8% had moderate-to-severe disease; 75.7 versus 54.3% were taking disease-modifying treatment; 87.7 versus 58.7% had received an MRI in the past year. Most active cases (n = 1116; 59.1%) were identified by MRI versus 239 (12.7%) by relapse and 534 (28.3%) by MRI plus relapse. In EXPAND-PBO, 263 patients were classified ‘active’ (≥1 relapse in 2 years before screening and/or ≥1 gadolinium-enhancing lesion) and 270 ‘non-active’ (no relapse in the 2 years before screening and no gadolinium-enhancing lesion[s]) at baseline; similar proportions of these groups had received disease-modifying treatment prior to placebo: 77.2 and 80.7%. Of non-active patients, 53.0% had disease activity on study; in these patients, 74.1% had disease activity identified by MRI, 8.4% by relapse, and 17.5% by MRI plus relapse. In patients classified non-active at baseline: age and percentage with Expanded Disability Status Scale score 6.0–6.5 were similar between patients with disease activity on study versus patients who remained non-active: 48 versus 52 years; 49.7 versus 56.7%, respectively. In real-world and clinical trial settings, MRI could be a better option than relapse for the identification of disease activity. However, in the real-world, fewer non-active patients had received an MRI in the last year than active patients, which is concerning given that most disease activity in EXPAND-PBO was identified via MRI. We highlight difficulties in consistently identifying disease activity and the negative implications of infrequent monitoring of non-active disease.
Going ‘meta’: a systematic review of metacognition and functional neurological disorder
Authors: Sadnicka Anna , Strudwick Ann-Marie , Grogan John P , Manohar Sanjay , Nielsen Glenn 
Published: January 2025

Abstract
In functional neurological disorder (FND), there is a fundamental disconnect between an apparently intact nervous system and the individuals’ ability to consistently perform motor actions, perceive sensory signals, and/or access effective cognition. Metacognition, the capacity to self-evaluate cognitive performance, appears highly relevant to FND pathophysiology. Poor metacognition is a potential mechanism via which abnormal models of self and the state of the world could arise and persist unchecked. There is therefore a justified enthusiasm that studies of metacognition may give substance to FND’s intangible nature. However, many assume an impairment in metacognition even though experimental studies are still in their infancy. This systematic review provides an analytical checkpoint of the evidence after the first five years of experimental work. We firstly summarise current methods for testing metacognition, prerequisite knowledge that allows readers to independently evaluate the evidence. Using preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) approach we then screened the 21 articles on this topic and review the experimental data of the eight studies that specifically tested metacognition in subjects with FND. Questionnaire metrics used to estimate global metacognition and general confidence in FND revealed a mixed picture of low or normal confidence. Of the five studies that used performance-controlled metrics, the gold-standard to estimate local metacognition in FND, four found metacognition to be equivalent to healthy controls and one paper supported impaired metacognition. We consequently try and broaden the debate and discuss alternative headline scenarios. We review how positive studies may offer insight and debate whether null studies could represent false negatives. However, since most studies find equivalent metacognition to controls, we also discuss whether metacognition could be intact and how this could inform mechanistic models of FND and have potential clinical utility. In summary, this review highlights signal of interest within the data, exposes current limitations and flags the many open questions.
Mesoporous materials 2.0: innovations in metals and chalcogenides for future applications
Authors: Han Minsu , Nagaura Tomota , Kim Jeonghun , Alshehri Saad M , Ahamad Tansir , Bando Yoshio , Alowasheeir Azhar , Asakura Yusuke , Yamauchi Yusuke 
Published: January 2025

Abstract
Incorporating mesoporous structures into various materials can provide abundant active sites and facilitate smooth diffusion, and their effectiveness has been demonstrated across a range of material types. However, despite the development of numerous mesoporous materials, first-generation mesoporous materials (e.g., silica-based compositions) have limited applications due to their poor electrical conductivity and limited compositional diversity, necessitating additional processing for widespread utilization. Our group first proposed the synthesis of mesoporous metals using a solution-based soft-templating method based on self-assembly of micelles, marking a significant advancement in mesoporous materials. This effective process has recently been extended to the synthesis of mesoporous metals and chalcogenides. Chalcogenides have garnered significant attention due to their intriguing optical, electrical, and electrochemical properties arising from their distinctive electronic structures. Mesoporous chalcogenides have been found to effectively enhance these properties. This paper provides a comprehensive review of the synthesis of mesoporous metals and chalcogenides—representing second-generation mesoporous materials (mesoporous materials 2.0)—with specific examples. Our goal is to inform readers about second-generation mesoporous materials and provide insights for further research.
Improvement in serum eosinophilia is observed in clinical responders to ustekinumab but not adalimumab in inflammatory bowel disease
Authors: Wong Emily C L , Dulai Parambir S , Marshall John K , Jairath Vipul , Reinisch Walter , Narula Neeraj 
Published: January 2025

Abstract

Introduction
In inflammatory bowel disease (IBD), the number of eosinophils increases in the lamina propria of the intestinal tract, but their specific patho-mechanistic role remains unclear. Elevated blood eosinophil counts in active IBD suggest their potential as biomarkers for predicting response to biological therapies. This study evaluates blood eosinophil count trends and their predictive value for clinical response and endoscopic improvement in patients with IBD receiving ustekinumab or adalimumab induction therapy.

Methods
Participant-level data from phase 3 and 4 clinical trials (UNIFI, SEAVUE, VARSITY) evaluating ustekinumab and adalimumab for moderate–severe Crohn’s disease (CD) and ulcerative colitis (UC) were used. The primary outcome was clinical response, defined by reductions in disease activity scores. Eosinophil counts were compared between responders and non-responders at multiple time points using t-tests. Logistic regression assessed the odds of achieving a clinical response based on baseline eosinophil counts.

Results
Among patients treated with ustekinumab for UC, responders had significantly higher baseline eosinophil counts compared to non-responders (0.21 × 109/L vs 0.18 × 109/L, P = .042). By week 8, responders showed a greater absolute (−0.07 × 109/L vs −0.01 × 109/L, P &lt; .001) and percent decline (−33.33% vs −5.55%, P = .027) in eosinophil counts. In CD, ustekinumab responders also had higher baseline eosinophil counts and showed significant reductions by week 8. However, no significant differences in eosinophil counts were observed among CD patients treated with adalimumab or UC patients treated with vedolizumab.

Conclusion
Eosinophil reduction was identified as a marker for early response to ustekinumab in both UC and CD, but not adalimumab. No difference was observed among UC patients treated with vedolizumab either. Targeting the IL-12/IL-23 pathway may be more effective in managing eosinophil-associated inflammation in IBD.
Lung ultrasound in neonates and children with cardiac diseases with focus on post cardiac surgical period: time for systematic use—an expert opinion report by the Association for European Paediatric and Congenital Cardiology Imaging Working Group
Authors: Cantinotti Massimiliano , Di Salvo Giovanni , Voges Inga , Raimondi Francesca , Greil Gerald , Garrido Almudena Ortiz , Grotenhuis Heynric B , McMahon Colin J 
Published: January 2025

Abstract

Background
Despite lung ultrasound (LUS) gaining consensus for the diagnosis of pulmonary complication in paediatric acute care setting and in adult cardiology, its use in paediatric cardiology remains limited.

Aim
The aim of the present investigation is to provide an expert opinion on the applications of LUS in neonates and children with congenital heart disease, with a special focus on the post-surgical period.

Methods and Results
A complete guide for identification of landmarks and major signs (A and B lines) and their characteristics is provided. Diagnostic criteria, tips, and tricks for the diagnosis, and differential diagnosis of common pulmonary diseases such as pleural effusion, pneumonia, and consolidation are provided. To perform diagnosis of pneumothorax is illustrated. Applications of LUS for evaluation of hemidiaphragm motility and for a comprehensive assessment of retrosternal area are also discussed. The use of LUS for guidance of minor, common interventional procedures such as lung recruitment and drainage insertion is also described. The report also highlights current gaps of knowledge, including the difficulty for quantitative estimation of pleural effusion and atelectasis, and future prospective.

Conclusion
There is sufficient evidence to support a systematic use of LUS for the diagnosis and follow-up of neonates and children with cardiac disease especially those undergoing paediatric cardiac surgery. LUS is an easy, accurate, fast, cheap, and radiation-free tool that should become a routine in daily practice.
Impact of sex hormones on pheochromocytomas, paragangliomas, and gastroenteropancreatic neuroendocrine tumors
Authors: Wang Katharina , Fischer Alessa , Maccio Umberto , Zitzmann Kathrin , Robledo Mercedes , Lauseker Michael , Bauer Jana , Bechmann Nicole , Gahr Simon , Maurer Julian , Peischer Lea , Reul Astrid , Nieß Hanno , Zimmermann Petra , Ilmer Matthias , Schilbach Katharina , Knösel Thomas , Kroiss Matthias , Fassnacht Martin , Müller Simon A , Morand Gregoire B , Huber Alexander , Vetter Diana , Lehmann Kuno , Kulcsar Zsolt , Mohr Hermine , Pellegata Natalia S , Hantel Constanze , Reincke Martin , Beuschlein Felix , Pacak Karel , Grossman Ashley B , Auernhammer Christoph J , Nölting Svenja 
Published: January 2025

Abstract

Objective
The effects of sex hormones remain largely unexplored in pheochromocytomas and paragangliomas (PPGLs) and gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

Methods
We evaluated the effects of estradiol, progesterone, Dehydroepiandrosterone sulfate (DHEAS), and testosterone on human patient-derived PPGL/GEP-NET primary culture cell viability (n = 38/n = 12), performed next-generation sequencing and immunohistochemical hormone receptor analysis in patient-derived PPGL tumor tissues (n = 36).

Results
In PPGLs, estradiol and progesterone (1 µm) demonstrated overall significant antitumor effects with the strongest efficacy in PPGLs with NF1 (cluster 2) pathogenic variants. Estrogen receptor alpha (ERα) positivity was detected in 11/36 PPGLs, including 4/4 head-and-neck paragangliomas (HNPGLs). ERα–positive tumors responded with a significant cell viability decrease to estradiol. DHEAS and testosterone (1 µm) displayed no effects, but higher doses of testosterone (10 µm) demonstrated significant antitumor effects, including a pheochromocytoma lung metastasis with strong androgen receptor positivity (30%). Driven by the antitumor effects of estrogen, we evaluated G-protein-coupled estrogen receptor (GPER) agonist G-1 as a potential therapeutic option for PPGLs and found strong significant antitumor potential, with the strongest efficacy in tumors with NF1 pathogenic variants. Moreover, we detected sex-related differences—tumors from male patients showed significantly stronger responsivity to G-1 compared with tumors from female patients. In GEP-NETs, sex hormones showed overall no effects, especially no tumor growth-promoting effects.

Conclusion
We provide novel data on the effects of elevated sex hormone levels, potentially seen during pregnancy or hormone replacement therapy, on PPGL/GEP-NET tumor growth. G-1 might offer a novel therapeutic approach for some PPGLs depending on patient’s sex and the individual tumor’s genetic/molecular background. All HNPGLs showed ERα positivity.
Tumour necrosis factor alpha-induced protein 3-interacting protein 3 overexpression protects against arrhythmogenic remodelling in the heart failure mice
Authors: Yang Hongjie , Shen Xiaoyan , Wang Huibo , Shuai Wei 
Published: January 2025

Abstract

Aims
Ventricular arrhythmias (VAs), which can lead to sudden cardiac death, are the primary cause of mortality in patients with heart failure (HF). However, the precise mechanisms underlying these arrhythmias are not well understood. Recent studies have implicated tumour necrosis factor alpha-induced protein 3-interacting protein 3 (TNIP3) in pathological cardiac hypertrophy. Nevertheless, its role in isoproterenol (ISO)-associated VAs remains elusive.

Methods and results
We overexpressed TNIP3 in the myocardium using an adeno-associated virus 9 system, administered via tail vein injection. C57BL/6 mice received daily subcutaneous injections of ISO for two consecutive weeks to establish an HF model. We performed histopathology and electrophysiological studies to assess ventricular structural remodelling, electrical remodelling, and susceptibility to VAs. Additionally, RNA sequencing (RNA-Seq) and western blot analysis were conducted to elucidate the underlying mechanisms. The expression of TNIP3 was up-regulated following ISO treatment. TNIP3 overexpression significantly reversed ISO-induced cardiac dysfunction, fibrosis, electrical remodelling, and VAs susceptibility. Accordingly, RNA-Seq identifies that the inflammatory response takes an important role in ISO-induced Vas, and TNIP3 overexpression could alleviate ISO-induced cardiac proinflammatory response by promoting M1 to M2 macrophage polarization. Mechanistically, PI3K/Akt/NF-κB signalling is responsible for the protective effect of TNIP3 overexpression on ISO-induced HF. And PI3K/Akt signalling activation offset the protective effect of TNIP3 overexpression on ISO-induced cardiac inflammation and VAs.

Conclusion
The findings of this study highlight the critical role of TNIP3 in ISO-associated cardiac remodelling and VAs, which are induced by the inhibited activation of the PI3K/Akt/NF-κB signalling pathway.