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| Open AccessCDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer
Finding biomarkers for targeted therapy is a promising approach to treat cancer. Here, the authors show that in breast cancer preclinical models and patients, CDK12 promotes tumourigenesis but induces selective vulnerability to therapies that target folate one-carbon metabolism.
- M. G. Filippone
- , D. Gaglio
- & S. Pece
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Article
| Open AccessSerum metabolome associated with severity of acute traumatic brain injury
Traumatic brain injury is associated with changes to the metabolome. Here the authors show that acute traumatic brain injury has distinctive serum metabolic patterns which may suggest protective changes of systemic lipid metabolism aiming to maintain lipid homeostasis in the brain.
- Ilias Thomas
- , Alex M. Dickens
- & Tommaso Zoerle
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Article
| Open AccessContribution of rare whole-genome sequencing variants to plasma protein levels and the missing heritability
Despite the success of genome-wide association studies, much of the genetic contribution to complex traits remains unexplained. Here, the authors identify effects by rare variants on plasma proteins, and estimate the contribution of rare variants to the heritability.
- Marcin Kierczak
- , Nima Rafati
- & Åsa Johansson
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Article
| Open AccessHeterogeneity of neuroendocrine transcriptional states in metastatic small cell lung cancers and patient-derived models
Molecular subtypes of small cell lung cancer characterized by neuroendocrine differentiation have been described in cell lines and primary tumors. The clinical implications of neuroendocrine subtypes in metastatic and relapsed tumors, and the extent to which the subtype distribution is recapitulated in patient-derived models remains unclear. Here, the authors integrated genomics and transcriptomics on 100 small cell cancers from a range of metastatic sites finding complex intra- and intertumoral heterogeneity, notably not recapitulated in patient-derived model systems, and distinct therapeutic vulnerabilities associated with neuroendocrine subtypes.
- Delphine Lissa
- , Nobuyuki Takahashi
- & Anish Thomas
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Article
| Open AccessGeneration of human islet cell type-specific identity genesets
Cell therapy to replace β-cells is a potential therapeutic avenue to treat diabetes, but the production of insulin-secreting replacement cells requires reliable tools to assess islet cellular identity. Here the authors use single-cell transcriptomics meta-analysis to construct gene sets that describe the identity of human α-, β-, γ- and δ-cells.
- Léon van Gurp
- , Leon Fodoulian
- & Pedro L. Herrera
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Article
| Open AccessUsing deep learning to predict abdominal age from liver and pancreas magnetic resonance images
Approaches to both determine abdominal age and identify risk factors for accelerated abdominal age will help delay the onset of several diseases. Here, the authors build an abdominal age predictor by training convolutional neural networks to predict abdominal age from liver and pancreas MRIs.
- Alan Le Goallec
- , Samuel Diai
- & Chirag J. Patel
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Article
| Open AccessA polygenic risk score for nasopharyngeal carcinoma shows potential for risk stratification and personalized screening
Polygenic Risk Scores (PRS) show promise for facilitating cancer risk stratification. Here, the authors performed a large genome-wide association study and develop a PRS for nasopharyngeal carcinoma, which could improve risk stratification and personalized screening.
- Yong-Qiao He
- , Tong-Min Wang
- & Wei-Hua Jia
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Article
| Open AccessPredictive biomarkers for survival benefit with ramucirumab in urothelial cancer in the RANGE trial
Identification of biomarkers to stratify patients who might benefit from treatment is needed to optimize targeted therapies. Here, based on an analysis of the RANGE trial (NCT02426125), the authors report potentially predictive biomarkers for survival benefit in patients with platinum-refractory advanced urothelial carcinoma treated with the anti-VEGFR2 monoclonal antibody ramucirumab.
- Michiel S. van der Heijden
- , Thomas Powles
- & Alexandra Drakaki
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Article
| Open AccessACKR3 regulates platelet activation and ischemia-reperfusion tissue injury
ACKR3 is a critical regulator of platelet-mediated thrombosis and organ injury following ischemia/reperfusion. Platelet ACKR3 surface expression is independently associated with all-cause mortality in patients with cardiovascular diseases.
- Anne-Katrin Rohlfing
- , Kyra Kolb
- & Meinrad Gawaz
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Article
| Open AccessSerum proteomics links suppression of tumor immunity to ancestry and lethal prostate cancer
Ancestry-related differences in immunobiology may explain the health disparities observed in prostate cancer patients, with men of African origin bearing the highest prostate cancer burden. By measuring immune-related proteins in serum samples, here the authors report that systemic cytokines linked to suppression of tumor immunity are upregulated in men of African ancestry and associated with reduced survival.
- Tsion Zewdu Minas
- , Julián Candia
- & Stefan Ambs
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Article
| Open AccessA hydrogen sulphide-responsive and depleting nanoplatform for cancer photodynamic therapy
Abnormal levels of intracellular hydrogen sulphide (H2S) have been associated with different pathological conditions, including cancer. Here the authors report the design of a H2S-responsive and -depleting nanoplatform that, combined with NIR-II photodynamic properties, can be used for H2S imaging and cancer therapy.
- Yuqi Zhang
- , Jing Fang
- & Haibin Shi
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Article
| Open AccessGenome-wide association studies of metabolites in Finnish men identify disease-relevant loci
The Finnish population is enriched for genetic variants which are rare in other populations. Here, the authors find new genetic loci associated with 1391 circulating metabolites in 6136 Finnish men, demonstrating that metabolite genetic associations can help elucidate disease mechanisms.
- Xianyong Yin
- , Lap Sum Chan
- & Michael Boehnke
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Article
| Open AccessDissociation of tau pathology and neuronal hypometabolism within the ATN framework of Alzheimer’s disease
In Alzheimer’s disease (AD) tau and neurodegeneration have complex regional relationships. Here, the authors show neuronal hypometabolism discordant with tau burden defines functional resilience or susceptibility to Alzheimer’s pathology via limbic/cortical axes. Susceptible groups have faster cognitive decline and evidence of non-Alzheimer’s pathologies.
- Michael Tran Duong
- , Sandhitsu R. Das
- & Ilya M. Nasrallah
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Article
| Open AccessTau deposition patterns are associated with functional connectivity in primary tauopathies
Tau pathology drives neuronal dysfunction in 4- repeat tauopathies. Here, the authors combine tau-PET, resting-state fMRI and histopathology data, to show that brain connectivity is associated with tau deposition patterns in 4-repeat tauopathies.
- Nicolai Franzmeier
- , Matthias Brendel
- & Michael Ewers
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Article
| Open AccessAutoantibodies targeting GPCRs and RAS-related molecules associate with COVID-19 severity
COVID-19, similarly to systemic autoimmune diseases, is characterised by the presence of autoantibodies. Authors show here that the abundance and network signature of autoantibodies targeting G protein-coupled receptors and RAS-related proteins are altered in COVID-19 patients, and the level of disruption marks clinical severity.
- Otavio Cabral-Marques
- , Gilad Halpert
- & Yehuda Shoenfeld
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Article
| Open AccessQuantifying arousal and awareness in altered states of consciousness using interpretable deep learning
The authors propose an explainable consciousness indicator using deep learning to quantify arousal and awareness under sleep, anesthesia, and in patients with disorders of consciousness.
- Minji Lee
- , Leandro R. D. Sanz
- & Seong-Whan Lee
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Article
| Open AccessMicrobial-driven preterm labour involves crosstalk between the innate and adaptive immune response
Gaining mechanistic insight into the microbiological and immunological factors that are associated with spontaneous preterm birth is important for the development of prevention strategies. Here authors show that the complement system in conjunction with specific vaginal microbial and associated immunological changes are contributing to this condition.
- Denise Chan
- , Phillip R. Bennett
- & Lynne Sykes
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Article
| Open AccessDihydroceramide- and ceramide-profiling provides insights into human cardiometabolic disease etiology
Among lipid classes, ceramides are linked to impaired cardiometabolic health. Here the authors report the association of specific ceramides and dihydroceramides on the risk of developing type 2 diabetes and or cardiovascular disease in a prospective population cohort.
- C. Wittenbecher
- , R. Cuadrat
- & M. B. Schulze
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Article
| Open AccessStratification of hospitalized COVID-19 patients into clinical severity progression groups by immuno-phenotyping and machine learning
Developing predictive methods to identify patients with high risk of severe COVID-19 disease is of crucial importance. Authors show here that by measuring anti-SARS-CoV-2 antibody and cytokine levels at the time of hospital admission and integrating the data by unsupervised hierarchical clustering/machine learning, it is possible to predict unfavourable outcome.
- Yvonne M. Mueller
- , Thijs J. Schrama
- & Peter D. Katsikis
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Article
| Open AccessAn efficient urine peptidomics workflow identifies chemically defined dietary gluten peptides from patients with celiac disease
Gluten peptides from wheat enter the bloodstream and are excreted in urine but are yet to be chemically characterised. Here, the authors show by mass spectrometry that quantitative and qualitative differences in urinary peptides can be detected between healthy people and patients with celiac disease.
- Brad A. Palanski
- , Nielson Weng
- & Joshua E. Elias
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Article
| Open AccessGut metagenome associations with extensive digital health data in a volunteer-based Estonian microbiome cohort
Here, the authors present results of the Estonian Microbiome Project, which combines metagenomics and electronic health data from 2500 individuals, expanding microbiome-host interactions in particular with regards to effects of long-term antibiotic usage on the microbiome across diseases.
- Oliver Aasmets
- , Kertu Liis Krigul
- & Elin Org
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Article
| Open AccessSingle-cell analysis of human glioma and immune cells identifies S100A4 as an immunotherapy target
Glioblastoma (GBM) is an immune cold tumour that is refractory to immunotherapy. Here, the authors identify molecular phenotypes of immune-suppressive and -promoting myeloid cells in GBM through single cell RNA sequencing and propose S100A4 as a regulator of immune suppressive T and myeloid cells in GBM.
- Nourhan Abdelfattah
- , Parveen Kumar
- & Kyuson Yun
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Article
| Open AccessImmunoglobulin signature predicts risk of post-acute COVID-19 syndrome
Studying a prospective cohort, the authors develop and validate a predictive score for post-acute COVID-19 syndrome, also known as long-COVID. This score relies on an immunoglobulin signature and is independent of timepoint of blood sampling.
- Carlo Cervia
- , Yves Zurbuchen
- & Onur Boyman
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Article
| Open AccessCoding and regulatory variants are associated with serum protein levels and disease
Finding the genetic basis of protein expression can elucidate the genetic mechanisms of disease. Here, the authors link low-frequency and common DNA sequence variants to thousands of serum proteins, finding genetic overlap between circulating proteins and a wide range of common diseases.
- Valur Emilsson
- , Valborg Gudmundsdottir
- & Vilmundur Gudnason
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Comment
| Open AccessImmune-related adverse events and the balancing act of immunotherapy
The benefit from immune checkpoint inhibitors is tempered by immunologic toxicities, which involve diverse organs, have varying biology, onset time, and severity. Herein, we identify important areas of controversy and open research questions in the field of immune-related toxicity.
- Michael Conroy
- & Jarushka Naidoo
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Article
| Open AccessAge influences on the molecular presentation of tumours
Ageing is a known risk factor in the development of cancers, but its association with molecular alterations is not fully explored. Here, the authors analyse pan-cancer age-associated molecular alterations in datasets from the TCGA, PCAWG and AACR-GENIE projects and identify prognostic biomarkers.
- Constance H. Li
- , Syed Haider
- & Paul C. Boutros
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Article
| Open AccessmolBV reveals immune landscape of bacterial vaginosis and predicts human papillomavirus infection natural history
Here, Burk et al. develop an algorithm to diagnose bacterial vaginosis (BV) using the 16S rRNA gene, called molBV, which they use to profile the inflammatory landscape of BV and predict progression of human papillomavirus infection to cervical pre-cancer.
- Mykhaylo Usyk
- , Nicolas F. Schlecht
- & Robert D. Burk
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Article
| Open AccessDNA methylation aging and transcriptomic studies in horses
Methylation levels of specific sites in the genome is correlated with aging. Here the authors develop a human-horse clock which could assist in translating anti-aging interventions from humans to horses and vice versa.
- Steve Horvath
- , Amin Haghani
- & Carrie J. Finno
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Article
| Open AccessSmart facemask for wireless CO2 monitoring
While facemasks are recommended to prevent the spread of SARS-CoV-2, potential adverse effects may occur upon prolonged usage. Here the authors develop and evaluate an opto-chemical sensor incorporated into a smart FFP2-type facemask for wireless, real-time CO2 monitoring.
- P. Escobedo
- , M. D. Fernández-Ramos
- & A. J. Palma
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Article
| Open AccessVascular and blood-brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue
The vascular, cellular and molecular changes underlying sex differences in mood disorders are unclear. Here, the authors show that blood-brain barrier dysfunction modulates anxiety- and depressive-like behaviors in female mice and endothelium-specific changes associated with maladaptive responses compared to resilience to stress.
- Laurence Dion-Albert
- , Alice Cadoret
- & Caroline Menard
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Article
| Open AccessLipidomic profiling of human serum enables detection of pancreatic cancer
Patients with pancreatic cancer have a poor prognosis, more research is required to identify the disease at an earlier stage. Here, the authors use lipid profiles of blood samples and show that they can distinguish patients with pancreatic cancer from healthy controls.
- Denise Wolrab
- , Robert Jirásko
- & Michal Holčapek
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Article
| Open AccessProteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction
Multi-inflammatory syndrome in children (MIS-C) can be associated with SARS-CoV-2 infection but can also be similar to other inflammatory syndromes. Here the authors characterise the plasma proteome phenotype in MIS-C and compare to other SARS-CoV-2 related syndromes and find disproportionately high IFN-γ responses in MIS-C patients.
- Caroline Diorio
- , Rawan Shraim
- & Edward M. Behrens
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Article
| Open AccessMassive image-based single-cell profiling reveals high levels of circulating platelet aggregates in patients with COVID-19
The authors report the landscape of circulating platelet aggregates in COVID-19 obtained by massive single-cell image-based profiling and temporal monitoring to elucidate the underlying process of COVID-19-assocaited microvascular thrombosis.
- Masako Nishikawa
- , Hiroshi Kanno
- & Keisuke Goda
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Article
| Open AccessA deep learning framework identifies dimensional representations of Alzheimer’s Disease from brain structure
Alzheimer’s disease is heterogeneous in its neuroimaging and clinical phenotypes. Here the authors present a semi-supervised deep learning method, Smile-GAN, to show four neurodegenerative patterns and two progression pathways providing prognostic and clinical information.
- Zhijian Yang
- , Ilya M. Nasrallah
- & Balebail Ashok Raj
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Article
| Open AccessTherapeutic vulnerability to PARP1,2 inhibition in RB1-mutant osteosarcoma
RB1 mutations are seen in 40-60% of sporadic osteosarcoma. Here, the authors demonstrate a selective sensitivity to PARP inhibitors in RB1-mutated osteosarcoma-derived cell lines that is not associated with canonical signatures indicative of a homologous recombination defect.
- Georgia Zoumpoulidou
- , Carlos Alvarez-Mendoza
- & Sibylle Mittnacht
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Article
| Open AccessMapping the serum proteome to neurological diseases using whole genome sequencing
Serum proteins are easily accessible biomarkers and drug targets. Here, the authors use whole genome sequencing data to describe the genetic architecture of neurologically-relevant serum proteins and establish causal protein-neurological disease relationships.
- Grace Png
- , Andrei Barysenka
- & Eleftheria Zeggini
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Article
| Open AccessRisk-stratification of febrile African children at risk of sepsis using sTREM-1 as basis for a rapid triage test
Identification of febrile children at risk of death in low-resource settings can improve survival, but tools for their prompt recognition are lacking. Here, the authors show that sTREM-1 measured at clinical presentation predicts in-hospital mortality in febrile children in Uganda.
- Aleksandra Leligdowicz
- , Andrea L. Conroy
- & Kevin C. Kain
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Article
| Open AccessDynamic recurrence risk and adjuvant chemotherapy benefit prediction by ctDNA in resected NSCLC
ctDNA has been shown to identify minimal residual disease (MRD) and is thus dynamically monitored in different types of tumours. Here, the authors show that serial longitudinal ctDNA analysis can be used as a tool to detect MRD, inform the use of adjuvant therapy, and predict recurrence risk in lung cancer.
- Bin Qiu
- , Wei Guo
- & Jie He
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Article
| Open AccessImmune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma
PD-1 blockade is effective for only a subset of patients with cutaneous T cell lymphomas. Here, the authors report a spatial biomarker that uses immune and cancer cell topography to predict response to PD-1 blockade in this disease.
- Darci Phillips
- , Magdalena Matusiak
- & Garry P. Nolan
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Article
| Open AccessSoluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer
The emergence of acquired resistance to standard platinum-etoposide chemotherapy in small cell lung cancer (SCLC) is a common event. Here, the authors using paired pre-treatment and post-chemotherapy circulating tumour cell patient-derived explant (CDX) models reveal a mechanism of drug resistance in SCLC mediated by Notch and nitric oxide activation of soluble guanylate cyclase signalling.
- Maximilian W. Schenk
- , Sam Humphrey
- & Kristopher K. Frese
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Article
| Open AccessFocal amplifications are associated with chromothripsis events and diverse prognoses in gastric cardia adenocarcinoma
The role of focal amplifications and extrachromosomal DNA (ecDNA) is unknown in gastric cardia adenocarcinoma (GCA). Here, the authors identify frequent focal amplifications and ecDNAs in Chinese GCA patient samples, as well as the potential associations of these alterations with prognosis and dietary habits.
- Xue-Ke Zhao
- , Pengwei Xing
- & Li-Dong Wang
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Article
| Open AccessGenomic signatures define three subtypes of EGFR-mutant stage II–III non-small-cell lung cancer with distinct adjuvant therapy outcomes
Adjuvant gefitinib improves outcomes in non-small cell lung cancer (NSCLC) patients compared to chemotherapy, but not in all cases. Here, the authors find genomic biomarkers of response to gefitinib in NSCLC patients from the ADJUVANT trial, and propose a score to stratify them by potential benefit from the treatment.
- Si-Yang Liu
- , Hua Bao
- & Yi-Long Wu
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Article
| Open AccessRAB5A expression is a predictive biomarker for trastuzumab emtansine in breast cancer
Antibody Drug Conjugates (ADCs) are emerging in the field of precision cancer medicine. Here, the authors suggest using endocytosis as a predictive biomarker for response
- Olav Engebraaten
- , Christina Yau
- & Anette Weyergang
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Article
| Open AccessNeoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2+ breast cancer in the adaptively randomized I-SPY2 trial
HER2-targeted therapy improves patient’s outcome in early breast cancer. Here, the authors present the efficacy and biomarker analysis of two HER2-targeted combinations (ado-trastuzumab emtansine plus pertuzumab and paclitaxel, trastuzumab and pertuzumab) in the context of the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence.
- Amy S. Clark
- , Christina Yau
- & Angela M. DeMichele
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Article
| Open AccessHigh-coverage metabolomics uncovers microbiota-driven biochemical landscape of interorgan transport and gut-brain communication in mice
The gut microbiota harbours neuroactive potential with links to neurological disorders. Here, the authors apply global metabolomics with an integrated annotation strategy to comparatively profile fecal, blood serum and cerebral cortical brain tissues of eight-week-old germ-free mice vs. age-matched specific-pathogen-free mice, providing a snapshot of the metabolome status linked to the gut-brain axis.
- Yunjia Lai
- , Chih-Wei Liu
- & Kun Lu
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Article
| Open AccessPathway signatures derived from on-treatment tumor specimens predict response to anti-PD1 blockade in metastatic melanoma
Gene signatures that predict response to immune checkpoint blockade (ICB) therapies in melanoma have been based on preclinical models and pre-treatment samples. Here the authors develop pathway-based signatures to predict ICB response in melanoma using on-treatment samples, leading to improved performance.
- Kuang Du
- , Shiyou Wei
- & Gao Zhang
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Article
| Open AccessDirect on-swab metabolic profiling of vaginal microbiome host interactions during pregnancy and preterm birth
Here, the authors apply DESI-MS, a sample preparation-free, direct on-swab mass spectrometry analytical tool, to profile the cervicovaginal metabolome of two independent cohorts of pregnant women and, combined with matched metataxonomic and immuno-profiling data, show that DESI-MS predicts vaginal microbiota composition and local inflammatory status associated with preterm birth and clinical interventions used during pregnancy.
- Pamela Pruski
- , Gonçalo D. S. Correia
- & David A. MacIntyre
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Article
| Open AccessFinger sweat analysis enables short interval metabolic biomonitoring in humans
Biomonitoring of sweat from fingertips overcomes current limitations in time-resolved metabolomic profiling of humans and may prove to become a powerful, noninvasive tool for precision medicine. Here, in a feasibility study of short interval sampling of sweat from fingertips, the authors assay individual dynamic metabolic patterns of endogenous and exogenous molecules.
- Julia Brunmair
- , Mathias Gotsmy
- & Christopher Gerner
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Article
| Open AccessHigh-spatial and colourimetric imaging of histone modifications in single senescent cells using plasmonic nanoprobes
The authors demonstrate a colourimetric imaging method using plasmonic nanoparticles for visualisation of heterochromatin histone markers. Based on the distance-dependent coupling effect, resulting in spectral shifts, they observe reorganisation of histone markers caused by oncogene-induced senescence.
- Hyun Ji An
- , Yun Kim
- & Inhee Choi