tbuckley/cabot-search huggingface dataset:
Ethnic variations in metabolic syndrome components and their associations with the gut microbiota: the HELIUS study
Authors: Manon Balvers, Marcus de Goffau, Natal van Riel, Bert-Jan van den Born, Henrike Galenkamp, Koos Zwinderman, Max Nieuwdorp, Evgeni Levin
Journal: Genome Medicine (2024)

Abstract Background The occurrence of metabolic syndrome (MetS) and the gut microbiota composition are known to differ across ethnicities yet how these three factors are interwoven is unknown. Also, it is unknown what the relative contribution of the gut microbiota composition is to each MetS component and whether this differs between ethnicities. We therefore determined the occurrence of MetS and its components in the multi-ethnic HELIUS cohort and tested the overall and ethnic-specific associations with the gut microbiota composition. Methods We included 16,209 treatment naïve participants of the HELIUS study, which were of Dutch, African Surinamese, South-Asian Surinamese, Ghanaian, Turkish, and Moroccan descent to analyze MetS and its components across ethnicities. In a subset ( n = 3443), the gut microbiota composition (16S) was associated with MetS outcomes using linear and logistic regression models. Results A differential, often sex-dependent, prevalence of MetS components and their combinations were observed across ethnicities. Increased blood pressure was commonly seen especially in Ghanaians, while South-Asian Surinamese and Turkish had higher MetS rates in general and were characterized by worse lipid-related measures. Regarding the gut microbiota, when ethnic-independent associations were assumed, a higher α-diversity, higher abundance of several ASVs (mostly for waist and triglyceride-related outcomes) and a trophic network of ASVs of Ruminococcaceae , Christensenellaceae , and Methanobrevibacter (RCM) bacteria were associated with better MetS outcomes. Statistically significant ethnic-specific associations were however noticed for α-diversity and the RCM trophic network. Associations were significant in the Dutch but not always in all other ethnicities. In Ghanaians, a higher α-diversity and RCM network abundance showed an aberrant positive association with high blood pressure measures compared to the other ethnicities. Even though adjustment for socioeconomic status-, lifestyle-, and diet-related variables often attenuated the effect size and/or the statistical significance of the ethnic-specific associations, an overall similar pattern across outcomes and ethnicities remained. Conclusions The occurrence of MetS characteristics among ethnicities is heterogeneous. Both ethnic-independent and ethnic-specific associations were identified between the gut microbiota and MetS outcomes. Across multiple ethnicities, a one-size-fits-all approach may thus be reconsidered in regard to both the definition and/or treatment of MetS and its relation to the gut microbiota.
Predicting the presence of coronary plaques featuring high-risk characteristics using polygenic risk scores and targeted proteomics in patients with suspected coronary artery disease
Authors: Peter Loof Møller, Palle Duun Rohde, Jonathan Nørtoft Dahl, Laust Dupont Rasmussen, Louise Nissen, Samuel Emil Schmidt, Victoria McGilligan, Daniel F. Gudbjartsson, Kari Stefansson, Hilma Holm, Jacob Fog Bentzon, Morten Bøttcher, Simon Winther, Mette Nyegaard
Journal: Genome Medicine (2024)

Abstract Background The presence of coronary plaques with high-risk characteristics is strongly associated with adverse cardiac events beyond the identification of coronary stenosis. Testing by coronary computed tomography angiography (CCTA) enables the identification of high-risk plaques (HRP). Referral for CCTA is presently based on pre-test probability estimates including clinical risk factors (CRFs); however, proteomics and/or genetic information could potentially improve patient selection for CCTA and, hence, identification of HRP. We aimed to (1) identify proteomic and genetic features associated with HRP presence and (2) investigate the effect of combining CRFs, proteomics, and genetics to predict HRP presence. Methods Consecutive chest pain patients ( n = 1462) undergoing CCTA to diagnose obstructive coronary artery disease (CAD) were included. Coronary plaques were assessed using a semi-automatic plaque analysis tool. Measurements of 368 circulating proteins were obtained with targeted Olink panels, and DNA genotyping was performed in all patients. Imputed genetic variants were used to compute a multi-trait multi-ancestry genome-wide polygenic score (GPS Mult ). HRP presence was defined as plaques with two or more high-risk characteristics (low attenuation, spotty calcification, positive remodeling, and napkin ring sign). Prediction of HRP presence was performed using the glmnet algorithm with repeated fivefold cross-validation, using CRFs, proteomics, and GPS Mult as input features. Results HRPs were detected in 165 (11%) patients, and 15 input features were associated with HRP presence. Prediction of HRP presence based on CRFs yielded a mean area under the receiver operating curve (AUC) ± standard error of 73.2 ± 0.1, versus 69.0 ± 0.1 for proteomics and 60.1 ± 0.1 for GPS Mult . Combining CRFs with GPS Mult increased prediction accuracy (AUC 74.8 ± 0.1 ( P = 0.004)), while the inclusion of proteomics provided no significant improvement to either the CRF (AUC 73.2 ± 0.1, P = 1.00) or the CRF + GPS Mult (AUC 74.6 ± 0.1, P = 1.00) models, respectively. Conclusions In patients with suspected CAD, incorporating genetic data with either clinical or proteomic data improves the prediction of high-risk plaque presence. Trial registration https://clinicaltrials.gov/ct2/show/NCT02264717 (September 2014).
Editorial Expression of Concern: Activated protein C inhibits tissue plasminogen activator–induced brain hemorrhage
Authors: Tong Cheng, Anthony. L Petraglia, Zhang Li, Meenakshisundaram Thiyagarajan, Zhihui Zhong, Zhenhua Wu, Dong Liu, Sanjay. B Maggirwar, Rashid Deane, José. A Fernández, Barbra LaRue, John. H Griffin, Michael Chopp, Berislav. V Zlokovic
Journal: Nature Medicine (2024)
The homeobox transcription factor DUXBL controls exit from totipotency
Authors: Maria Vega-Sendino, Felipe F. Lüttmann, Teresa Olbrich, Yanpu Chen, Carsten Kuenne, Paula Stein, Desiree Tillo, Grace I. Carey, Jiasheng Zhong, Virginia Savy, Lenka Radonova, Tianlin Lu, Bechara Saykali, Kee-Pyo Kim, Catherine N. Domingo, Leah Schüler, Stefan Günther, Mette Bentsen, Darko Bosnakovski, Hans Schöler, Michael Kyba, Tapan K. Maity, Lisa M. Jenkins, Mario Looso, Carmen J. Williams, Johnny Kim, Sergio Ruiz
Journal: Nature Genetics (2024)
Increased enhancer–promoter interactions during developmental enhancer activation in mammals
Authors: Zhuoxin Chen, Valentina Snetkova, Grace Bower, Sandra Jacinto, Benjamin Clock, Atrin Dizehchi, Iros Barozzi, Brandon J. Mannion, Ana Alcaina-Caro, Javier Lopez-Rios, Diane E. Dickel, Axel Visel, Len A. Pennacchio, Evgeny Z. Kvon
Journal: Nature Genetics (2024)
Co-dependent excitatory and inhibitory plasticity accounts for quick, stable and long-lasting memories in biological networks
Authors: Everton J. Agnes, Tim P. Vogels
Journal: Nature Neuroscience (2024)

The brain's functionality is developed and maintained through synaptic plasticity. As synapses undergo plasticity, they also affect each other. The nature of such 'co-dependency' is difficult to disentangle experimentally, because multiple synapses must be monitored simultaneously. To help understand the experimentally observed phenomena, we introduce a framework that formalizes synaptic co-dependency between different connection types. The resulting model explains how inhibition can gate excitatory plasticity while neighboring excitatory-excitatory interactions determine the strength of long-term potentiation. Furthermore, we show how the interplay between excitatory and inhibitory synapses can account for the quick rise and long-term stability of a variety of synaptic weight profiles, such as orientation tuning and dendritic clustering of co-active synapses. In recurrent neuronal networks, co-dependent plasticity produces rich and stable motor cortex-like dynamics with high input sensitivity. Our results suggest an essential role for the neighborly synaptic interaction during learning, connecting micro-level physiology with network-wide phenomena.
Can we learn from an imagined ransomware attack on a hospital at home platform?
Authors: Stephen Gilbert, Francesco Ricciardi, Tauseef Mehrali, Constantinos Patsakis
Journal: npj Digital Medicine (2024)

The hospital at home concept integrates key digital medicine technologies and concepts in a single platform approach, with telemedicine, wearables, and sensors. It could bring benefits to patients, who face lower risks from hospital infections and who want to be at home with their loved ones. Moreover, it may lead to efficiency savings, through its seamless integration of data flows, and therefore is likely to be an increasingly implemented model. But what happens when the platform succumbs to exploited platform/infrastructure vulnerabilities or cyber attacks like ransomware that have been weaponized to bring networked systems crashing down? Exploring the attack modes and their consequences could help prioritize adequate safeguards.
Virus-Induced Acute Respiratory Distress Syndrome Causes Cardiomyopathy Through Eliciting Inflammatory Responses in the Heart
Authors: Jana Grune, Geetika Bajpai, Pervin Tülin Ocak, Eva Kaufmann, Kyle Mentkowski, Steffen Pabel, Nina Kumowski, Fadi E. Pulous, Kim A. Tran, David Rohde, Shuang Zhang, Yoshiko Iwamoto, Gregory R. Wojtkiewicz, Claudio Vinegoni, Ursula Green, Filip K. Swirski, James R. Stone, Jochen K. Lennerz, Maziar Divangahi, Maarten Hulsmans, Matthias Nahrendorf
Journal: Circulation (2024)

Viral infections can cause acute respiratory distress syndrome (ARDS), systemic inflammation, and secondary cardiovascular complications. Lung macrophage subsets change during ARDS, but the role of heart macrophages in cardiac injury during viral ARDS remains unknown. Here we investigate how immune signals typical for viral ARDS affect cardiac macrophage subsets, cardiovascular health, and systemic inflammation.
AKAP12 Upregulation Associates With PDE8A to Accelerate Cardiac Dysfunction
Authors: Hanan Qasim, Mehrdad Rajaei, Ying Xu, Arfaxad Reyes-Alcaraz, Hala Y. Abdelnasser, M. David Stewart, Satadru K. Lahiri, Xander H.T. Wehrens, Bradley K. McConnell
Journal: Circulation Research (2024)

BACKGROUND: In heart failure, signaling downstream the β2-adrenergic receptor is critical. Sympathetic stimulation of β2-adrenergic receptor alters cAMP (cyclic adenosine 3′,5′-monophosphate) and triggers PKA (protein kinase A)-dependent phosphorylation of proteins that regulate cardiac function. cAMP levels are regulated in part by PDEs (phosphodiesterases). Several AKAPs (A kinase anchoring proteins) regulate cardiac function and are proposed as targets for precise pharmacology. AKAP12 is expressed in the heart and has been reported to directly bind β2-adrenergic receptor, PKA, and PDE4D. However, its roles in cardiac function are unclear. METHODS: cAMP accumulation in real time downstream of the β2-adrenergic receptor was detected for 60 minutes in live cells using the luciferase-based biosensor (GloSensor) in AC16 human-derived cardiomyocyte cell lines overexpressing AKAP12 versus controls. Cardiomyocyte intracellular calcium and contractility were studied in adult primary cardiomyocytes from male and female mice overexpressing cardiac AKAP12 (AKAP12 OX ) and wild-type littermates post acute treatment with 100-nM isoproterenol (ISO). Systolic cardiac function was assessed in mice after 14 days of subcutaneous ISO administration (60 mg/kg per day). AKAP12 gene and protein expression levels were evaluated in left ventricular samples from patients with end-stage heart failure. RESULTS: AKAP12 upregulation significantly reduced total intracellular cAMP levels in AC16 cells through PDE8. Adult primary cardiomyocytes from AKAP12 OX mice had significantly reduced contractility and impaired calcium handling in response to ISO, which was reversed in the presence of the selective PDE8 inhibitor (PF-04957325). AKAP12 OX mice had deteriorated systolic cardiac function and enlarged left ventricles. Patients with end-stage heart failure had upregulated gene and protein levels of AKAP12. CONCLUSIONS: AKAP12 upregulation in cardiac tissue is associated with accelerated cardiac dysfunction through the AKAP12-PDE8 axis.
Benefit of axicabtagene ciloleucel versus chemoimmunotherapy in older patients and/or patients with poor <scp>ECOG</scp> performance status with relapsed or refractory large B‐cell lymphoma after 2 or more lines of prior therapy
Authors: Matthew A. Lunning, Hai‐lin Wang, Zhen‐Huan Hu, Frederick L. Locke, Tanya Siddiqi, Caron A. Jacobson, Sairah Ahmed, David B. Miklos, Yi Lin, Brian T. Hill, Armin Ghobadi, Sattva S. Neelapu, Jason Westin, Chrisopher Dieyi, Polly Field, Harry Miao, Shilpa A. Shahani, Anik Patel, Clare Spooner, Christine Fu, David Muramoto, Hairong Xu, Marcelo C. Pasquini
Journal: American Journal of Hematology (2024)

Abstract Axicabtagene ciloleucel (axi‐cel) in trials has demonstrated favorable efficacy compared with historical controls after ≥2 lines of therapy for the treatment of relapsed or refractory (R/R) large B cell lymphoma (LBCL). Herein, we compared the real‐world effectiveness of axi‐cel with efficacy and effectiveness of chemoimmunotherapy (CIT) in patients aged ≥65 years and patients with Eastern Cooperative Oncology Group performance status (ECOG PS) of 2. A total of 1146 patients treated with commercial axi‐cel for R/R LBCL with ≥2 lines of prior therapy were included from the Center for International Blood and Marrow Transplantation Research prospective observational study, and 469 patients treated with CIT for R/R LBCL after ≥2 lines of prior therapy were included from SCHOLAR‐1 (an international, multicohort, retrospective study). After propensity score matching, at a median follow‐up of 24 months for patients receiving axi‐cel and 60 months for patients receiving CIT, 12‐month overall survival rates were 62% and 28%, respectively (hazard ratio, 0.30 [95% CI, 0.24–0.37]). Objective response rate (ORR) was 76% (complete response [CR] rate 58%) in patients receiving axi‐cel versus 28% (CR rate 16%) for those receiving CIT. A 57% difference in ORR (55% difference in CR rate) favoring axi‐cel over CIT was observed among patients aged ≥65 years. Increased magnitude of benefit in response rates for axi‐cel versus CIT was also observed among patients with ECOG PS = 2. These findings further support the broader use of axi‐cel in older patients and patients with ECOG PS = 2 with R/R LBCL.
Circular RNA as a source of neoantigens for cancer vaccines
Authors: Yi Ren, Thamizhanban Manoharan, Beijia Liu, Cyrus Zai Ming Cheng, Bei En Siew, Wai-Kit Cheong, Kai Yin Lee, Ian Jse-Wei Tan, Bettina Lieske, Ker-Kan Tan, Gloryn Chia
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background The effectiveness of somatic neoantigen-based immunotherapy is often hindered by the limited number of mutations in tumors with low to moderate mutation burden. Focusing on microsatellite-stable colorectal cancer (CRC), this study investigates the potential of tumor-associated circular RNAs (circRNAs) as an alternative source of neoepitopes in CRC. Methods Tumor-associated circRNAs in CRC were identified using the MiOncoCirc database and ribo-depletion RNA sequencing of paired clinical normal and tumor samples. Candidate circRNA expression was validated by quantitative real-time PCR (RT-qPCR) using divergent primers. TransCirc database was used for translation prediction. Human leukocyte antigen binding affinity of open reading frames from potentially translatable circRNA was predicted using pVACtools. Strong binders from messenger RNA-encoded proteins were excluded using BlastP. The immunogenicity of the candidate antigens was functionally validated through stimulation of naïve CD8 + T cells against the predicted neoepitopes and subsequent analysis of the T cells through enzyme-linked immunospot (ELISpot) assay, intracellular cytokine staining (ICS) and granzyme B (GZMB) reporter. The cytotoxicity of T cells trained with antigen peptides was further tested using patient-derived organoids. Results We identified a neoepitope from circRAPGEF5 that is upregulated in CRC tumor samples from MiOncoCirc database, and two neoepitopes from circMYH9, which is upregulated across various tumor samples from our matched clinical samples. The translation potential of candidate peptides was supported by Clinical Proteomic Tumor Analysis Consortium database using PepQuery. The candidate peptides elicited antigen-specific T cells response and expansion, evidenced by various assays including ELISpot, ICS and GZMB reporter. Furthermore, T cells trained with circMYH9 peptides were able to specifically target and eliminate tumor-derived organoids but not match normal organoids. This observation underscores the potential of circRNAs as a source of immunogenic neoantigens. Lastly, circMYH9 was enriched in the liquid biopsies of patients with CRC, thus enabling a detection-to-vaccination treatment strategy for patients with CRC. Conclusions Our findings underscore the feasibility of tumor-associated circRNAs as an alternative source of neoantigens for cancer vaccines targeting tumors with moderate mutation levels.
Multi-modal imaging for dynamic visualization of osteogenesis and implant degradation in 3D bioprinted scaffolds
Authors: Qian Feng, Kanwal Fatima, Ai Yang, Chenglin Li, Shuo Chen, Guang Yang, Xiaojun Zhou, Chuanglong He
Journal: Bioactive Materials (2024)

monitoring of bone regeneration enables timely diagnosis and intervention by acquiring vital biological parameters. However, an existing gap exists in the availability of effective methodologies for continuous and dynamic monitoring of the bone tissue regeneration process, encompassing the concurrent visualization of bone formation and implant degradation. Here, we present an integrated scaffold designed to facilitate real-time monitoring of both bone formation and implant degradation during the repair of bone defects. Laponite (Lap), CyP-loaded mesoporous silica (CyP@MSNs) and ultrasmall superparamagnetic iron oxide nanoparticles (USPIO@SiO
Diagnosis and prognosis of abnormal cardiac scintigraphy uptake suggestive of cardiac amyloidosis using artificial intelligence: a retrospective, international, multicentre, cross-tracer development and validation study
Authors: Clemens P Spielvogel, David Haberl, Katharina Mascherbauer, Jing Ning, Kilian Kluge, Tatjana Traub-Weidinger, Rhodri H Davies, Iain Pierce, Kush Patel, Thomas Nakuz, Adelina Göllner, Dominik Amereller, Maria Starace, Alice Monaci, Michael Weber, Xiang Li, Alexander R Haug, Raffaella Calabretta, Xiaowei Ma, Min Zhao, Julia Mascherbauer, Andreas Kammerlander, Christian Hengstenberg, Leon J Menezes, Roberto Sciagra, Thomas A Treibel, Marcus Hacker, Christian Nitsche
Journal: The Lancet Digital Health (2024)
High throughput screening of mesenchymal stromal cell morphological response to inflammatory signals for bioreactor-based manufacturing of extracellular vesicles that modulate microglia
Authors: Andrew M. Larey, Thomas M. Spoerer, Kanupriya R. Daga, Maria G. Morfin, Hannah M. Hynds, Jana Carpenter, Kelly M. Hines, Ross A. Marklein
Journal: Bioactive Materials (2024)

Due to their immunomodulatory function, mesenchymal stromal cells (MSCs) are a promising therapeutic with the potential to treat neuroinflammation associated with neurodegenerative diseases. This function is mediated by secreted extracellular vesicles (MSC-EVs). Despite established safety, MSC clinical translation has been unsuccessful due to inconsistent clinical outcomes resulting from functional heterogeneity. Current approaches to mitigate functional heterogeneity include 'priming' MSCs with inflammatory signals to enhance function. However, comprehensive evaluation of priming and its effects on MSC-EV function has not been performed. Furthermore, clinical translation of MSC-EV therapies requires significant manufacturing scale-up, yet few studies have investigated the effects of priming in bioreactors. As MSC morphology has been shown to predict their immunomodulatory function, we screened MSC morphological response to an array of priming signals and evaluated MSC-EV identity and potency in response to priming in flasks and bioreactors. We identified unique priming conditions corresponding to distinct morphologies. These conditions demonstrated a range of MSC-EV preparation quality and lipidome, allowing us to discover a novel MSC-EV manufacturing condition, as well as gain insight into potential mechanisms of MSC-EV microglia modulation. Our novel screening approach and application of priming to MSC-EV bioreactor manufacturing informs refinement of larger-scale manufacturing and enhancement of MSC-EV function.
Machine learning-enabled maternal risk assessment for women with pre-eclampsia (the PIERS-ML model): a modelling study
Authors: Tünde Montgomery-Csobán, Kimberley Kavanagh, Paul Murray, Chris Robertson, Sarah J E Barry, U Vivian Ukah, Beth A Payne, Kypros H Nicolaides, Argyro Syngelaki, Olivia Ionescu, Ranjit Akolekar, Jennifer A Hutcheon, Laura A Magee, Peter von Dadelszen, Mark A. Brown, Gregory K. Davis, Claire Parker, Barry N. Walters, Nelson Sass, J. Mark Ansermino, Vivien Cao, Geoffrey W. Cundiff, Emma C.M. von Dadelszen, M. Joanne Douglas, Guy A. Dumont, Dustin T. Dunsmuir, Jennifer A. Hutcheon, K.S. Joseph, Sayrin Lalji, Tang Lee, Jing Li, Kenneth I. Lim, Sarka Lisonkova, Paula Lott, Jennifer M. Menzies, Alexandra L. Millman, Lynne Palmer, Beth A. Payne, Ziguang Qu, James A. Russell, Diane Sawchuck, Dorothy Shaw, D. Keith Still, U. Vivian Ukah, Brenda Wagner, Keith R. Walley, Dany Hugo, The late Andrée Gruslin, George Tawagi, Graeme N. Smith, Anne-Marie Côté, Jean-Marie Moutquin, Annie B. Ouellet, Shoo K. Lee, Tao Duan, Jian Zhou, The late Farizah Haniff, Swati Mahajan, Amanda Noovao, Hanna Karjalainend, Alja Kortelainen, Hannele Laivuori, J. Wessel Ganzevoort, Henk Groen, Phillipa M. Kyle, M. Peter Moore, Barbra Pullar, Zulfiqar A. Bhutta, Rahat N. Qureshi, Rozina Sikandar, The late Shereen Z. Bhutta, Garth Cloete, David R. Hall, The late Erika van Papendorp, D. Wilhelm Steyn, Christine Biryabarema, Florence Mirembe, Annettee Nakimuli, John Allotey, Shakila Thangaratinam, Kypros H. Nicolaides, Olivia Ionescu, Argyro Syngelaki, Michael de Swiet, Laura A. Magee, Peter von Dadelszen, Ranjit Akolekar, James J. Walker, Stephen C. Robson, Fiona Broughton-Pipkin, Pamela Loughna, Manu Vatish, Christopher W.G. Redman, Sarah J.E. Barry, Kimberley Kavanagh, Tunde Montgomery-Csobán, Paul Murray, Chris Robertson, Eleni Z. Tsigas, Douglas A. Woelkers, Marshall D. Lindheimer, William A. Grobman, Baha M. Sibai, Mario Merialdi, Mariana Widmer
Journal: The Lancet Digital Health (2024)

Affecting 2-4% of pregnancies, pre-eclampsia is a leading cause of maternal death and morbidity worldwide. Using routinely available data, we aimed to develop and validate a novel machine learning-based and clinical setting-responsive time-of-disease model to rule out and rule in adverse maternal outcomes in women presenting with pre-eclampsia.