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| Open AccessTrained immunity in newborn infants of HBV-infected mothers
The ability to fight infections matures after birth and is thus termed ‘trained immunity’. Here the authors show that cord blood cells from hepatitis B virus-infected mothers respond more strongly to bacterial infections, suggesting that viral exposure in uteropromotes trained immunity in newborns.
- Michelle Hong
- , Elena Sandalova
- & Antonio Bertoletti
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| Open AccessRise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia
Genetic heterogeneity and clonal evolution contribute to cancer progression. Here Ma et al.use deep whole-exome sequencing to identify recurrently mutated pathways and clonal architecture in pediatric acute lymphoblastic leukaemia, shedding light on the evolutionary trajectory from diagnosis to relapse
- Xiaotu Ma
- , Michael Edmonson
- & Jinghui Zhang
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Impedance sensing device enables early detection of pressure ulcers in vivo
Sustained pressure on the skin reduces blood flow and causes wounds. Here the authors describe a flexible electronic ‘bandage’ that measures changes in tissue impedance spectra and detects early tissue damage in rats before it can be visualized, thus enabling possible prevention of pressure ulcers.
- Sarah L. Swisher
- , Monica C. Lin
- & Michel M. Maharbiz
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A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production
Receptor Interacting Protein Kinase 2 (RIPK2) mediates innate immune signalling in response to intracellular pathogens, but its aberrant activation contributes to autoimmune pathologies. Here Nachbur et al.describe a RIPK2 inhibitor that is effective in a mouse model of multiple sclerosis.
- Ueli Nachbur
- , Che A. Stafford
- & John Silke
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Genome-wide association study identifies a new susceptibility locus for cleft lip with or without a cleft palate
Cleft lip is one of the most common congenital birth defects with substantial impairments to quality of life. Here, Sun et al. identify a new locus associated with cleft lip in diverse Chinese populations.
- Yimin Sun
- , Yongqing Huang
- & Yinxue Yang
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| Open AccessPharmaceutical integrated stress response enhancement protects oligodendrocytes and provides a potential multiple sclerosis therapeutic
Current multiple sclerosis treatments focus on prevention of immune attack on oligodendrocytes and myelin. Here the authors show a different strategy to ameliorate disease in several mouse models, protecting oligodendrocytes from inflammation-induced death with an FDA-approved drug, guanabenz.
- Sharon W. Way
- , Joseph R. Podojil
- & Brian Popko
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The insulin and IGF1 receptor kinase domains are functional dimers in the activated state
In contrast to most receptor tyrosine kinases, the insulin and insulin-like growth factor-1 receptors are preformed, disulfide-linked dimers. Here the authors show that, after the two kinase domains of IR and IGF1R undergo autophosphorylation, they form a specific dimer to phosphorylate downstream substrates.
- M. Zulema Cabail
- , Shiqing Li
- & W. Todd Miller
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Genomic landscape of paediatric adrenocortical tumours
Pediatric adrenocortical carcinoma is a rare malignancy with poor prognosis. Here the authors analyse the genomes, exomes and transcriptomes of 37 such tumours and identify genetic alterations whose nature, timing and potential interactions are key events with prognostic significance in pediatric adrenocortical tumorigenesis.
- Emilia M. Pinto
- , Xiang Chen
- & Gerard P. Zambetti
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Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children
Food allergy is a growing clinical and public health burden. Here, the authors carry out a genome-wide association study in samples with well-defined allergies to a variety of foods, and identify the 6p21.32 region that significantly increases risk of developing peanut allergy.
- Xiumei Hong
- , Ke Hao
- & Xiaobin Wang
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Host genetic determinants of microbiota-dependent nutrition revealed by genome-wide analysis of Drosophila melanogaster
The gut microbiota affects animal nutrition, but it is unclear whether this effect depends on host genetic makeup. This study shows that host genotype modifies the gut microbiota’s impact on host nutrition, and identifies genetic determinants of this variation in the fruit fly.
- Adam J. Dobson
- , John M. Chaston
- & Angela E. Douglas
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Dendritic cells induce Th2-mediated airway inflammatory responses to house dust mite via DNA-dependent protein kinase
House dust mites are a common cause of allergic asthma. Here, the authors show that the Th2-mediated inflammatory responses triggered by mites in mouse airways are mediated by the activation of DNA-dependent protein kinase (DNA-PK) in dendritic cells.
- Amarjit Mishra
- , Alexandra L. Brown
- & Jay H. Chung
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The polymeric mucin Muc5ac is required for allergic airway hyperreactivity
Asthma is associated with mucus overproduction; however, the immunological consequences of excess mucus remain poorly understood. Here the authors show that formation of airway plugs by mucus promotes airway hypersensitivity, while deletion of mucous component Muc5acablates it independently of inflammation.
- Christopher M. Evans
- , Dorota S. Raclawska
- & Burton F. Dickey
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| Open AccessBotulinum toxin A complex exploits intestinal M cells to enter the host and exert neurotoxicity
It is unclear how ingested botulinum neurotoxin invades the host to cause illness. Here, the authors show that the toxin complex containing neurotoxin, hemagglutinin (HA), and NTNHA proteins traverses the epithelial barrier via HA-glycoprotein 2 interaction and endocytosis by Peyer’s patch microfold cells.
- Takuhiro Matsumura
- , Yo Sugawara
- & Yukako Fujinaga
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Identity of a Plasmodium lactate/H+ symporter structurally unrelated to human transporters
Malaria parasites generate metabolic energy through anaerobic glycolysis, yielding lactate and protons that are then secreted out of the parasite cell by an unknown transporter. Here, the authors identify and characterize a lactate/proton transporter that may be carrying out such function in Plasmodium.
- Binghua Wu
- , Janis Rambow
- & Eric Beitz
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| Open AccessTemporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition
Adaptive resistance is an emerging cause of chemotherapy failure in cancer. Here the authors show that adaptive resistance to taxanes is mediated by the upregulation of SFK/Hck survival signalling, and that sequential administration of taxanes and SFK/Hck inhibition restores tumor cell chemosensitivity.
- Aaron Goldman
- , Biswanath Majumder
- & Shiladitya Sengupta
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Pharmacological modulation of the AKT/microRNA-199a-5p/CAV1 pathway ameliorates cystic fibrosis lung hyper-inflammation
Hyperinflammation in cystic fibrosis has been linked to decreased levels of caveolin-1, resulting in higher LPS responsiveness of TLR4. Here the authors show that in a mouse model of cystic fibrosis decreased Akt results in accumulation of miR-199a-5p directly targeting caveolin-1 in macrophages.
- Ping-xia Zhang
- , Jijun Cheng
- & Emanuela M. Bruscia
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| Open AccessStructural characterization of a protective epitope spanning A(H1N1)pdm09 influenza virus neuraminidase monomers
Neuraminidase inhibitors offer a line of defence against flu infections, but resistance can occur even in the absence of prior exposure. Here Wan et al. describe the mode of action of CD6, a monoclonal antibody that protects against a common influenza strain, as a new therapeutic intervention model.
- Hongquan Wan
- , Hua Yang
- & Maryna C. Eichelberger
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Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases
TLR7 triggers immune responses upon sensing microbial RNA, and its endosomal localization is thought to prevent TLR7 activation by host RNA. Here, Kanno et al. show that TLR7 is also present on the surface of immune cells, and that anti-TLR7 antibody can prevent TLR7-mediated autoimmunity.
- Atsuo Kanno
- , Natsuko Tanimura
- & Kensuke Miyake
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Pharmacological inhibition of Dock5 prevents osteolysis by affecting osteoclast podosome organization while preserving bone formation
Small-molecule C21 inhibits Rac GTPase activation by Dock5, which decreases osteoclast activity in vitro. Using three mouse models where bone loss is caused by hyperactive osteoclasts, Vives et al. show that C21 treatment safely and efficiently prevents osteoporosis while preserving bone formation.
- Virginie Vives
- , Gaëlle Cres
- & Anne Blangy
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| Open AccessTargeting protein tyrosine phosphatase σ after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias
Chondroitin sulfate proteoglycans (CSP) in the myocardial scar inhibit the tissue’s reinnervation, rendering it prone to arrhythmia. Here the authors show that blocking the activity of the CSP receptor, protein tyrosine phosphatase receptor σ, promotes scar reinnervation and prevents arrhythmia in mice.
- R. T. Gardner
- , L. Wang
- & B. A. Habecker
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Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value
Triple-negative breast cancers (TNBCs) are a heterogeneous group of cancers with varying prognoses. Here, the authors carry out whole-genome methylation capture sequencing from TNBC samples and matched normal samples, and identify differentially methylated regions that define a potentially novel TNBC signature.
- Clare Stirzaker
- , Elena Zotenko
- & Susan J. Clark
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| Open AccessGeneralization of word meanings during infant sleep
In adults, oscillatory brain activity during sleep is related to memory consolidation. Here, the authors measure brain activity from infants who are exposed to novel word meanings, and show that infant sleep results in the retention and reorganization of recently encoded memories.
- Manuela Friedrich
- , Ines Wilhelm
- & Angela D. Friederici
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Coexistent ARID1A–PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling
ARID1A is frequently mutated in ovarian clear-cell carcinoma. Here the authors show that ARID1A loss in mice cooperates with PI3K activation to recapitulate the human disease, and implicate IL-6 signalling as the underlying mechanism.
- Ronald L. Chandler
- , Jeffrey S. Damrauer
- & Terry Magnuson
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Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness
Blindness due to retinal degeneration affects millions of people worldwide, but many disease-causing mutations remain unknown. Here the authors link mutations in the gene PNPLA6 with childhood blindness in seven families with retinal degeneration and show that the gene plays a role in photoreceptor survival in Drosophila.
- S. Kmoch
- , J. Majewski
- & R. K. Koenekoop
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Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour
Synthetic compounds that alter circadian rhythms have been shown to modulate energy expenditure and systemic metabolism in rodents. Here, the authors study the psychological effects of such compounds, and find synthetic REV-ERB agonists increase wakefulness and reduce anxiety-like behaviour in mice.
- Subhashis Banerjee
- , Yongjun Wang
- & Thomas P. Burris
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| Open AccessDietary cholesterol directly induces acute inflammasome-dependent intestinal inflammation
Chronic consumption of a Western-type diet leads to systemic inflammation of undefined origin, which contributes to metabolic disease. Here Progatzky et al. identify an immediate early step in the process by showing that dietary cholesterol rapidly activates inflammasomes in the gut epithelium.
- Fränze Progatzky
- , Navjyot J. Sangha
- & Margaret J. Dallman
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| Open AccessMitochondrial protein sorting as a therapeutic target for ATP synthase disorders
Effective treatment options for mitochondrial diseases are scarce. Here, Aiyar et al. identify the TIM23 mitochondrial protein sorting machinery as a potential intervention point for mitochondrial ATP synthase disorders.
- Raeka S. Aiyar
- , Maria Bohnert
- & Lars M. Steinmetz
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Somatic mutations in arachidonic acid metabolism pathway genes enhance oral cancer post-treatment disease-free survival
Chemical inhibitors of the tumour-progression promoting arachidonic acid metabolism pathway prolong post-treatment survival of cancer patients. Here the authors analyse sequence variation in oral cancer patients and show that loss-of-function mutations in this pathway prolong survival.
- Nidhan K. Biswas
- , Subrata Das
- & Partha P. Majumder
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Evidence for zoonotic potential of ovine scrapie prions
Scrapie, a form of prion disease that affects sheep and goats, is believed not to be transmissible to humans. Using transgenic mice expressing human prion protein as a model of cross-species prion transmission, the authors show that ovine scrapie may possess potential to be passed on to humans.
- Hervé Cassard
- , Juan-Maria Torres
- & Olivier Andréoletti
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The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice
Atrial fibrillation and heart failure often coexist but are difficult to treat. Here the authors report a therapeutic strategy for atrial fibrillation and heart failure in mice, based on the activating effect of a small molecule, BGP-15, on IGF1 receptor signalling.
- Geeta Sapra
- , Yow Keat Tham
- & Julie R. McMullen
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| Open AccessIntestinal epithelial MyD88 is a sensor switching host metabolism towards obesity according to nutritional status
Gut microbes are known to influence whole-body metabolism. Here Everard et al.show the adaptor protein MyD88 in intestinal epithelial cells is sensitive to changes in the diet and affects composition of the gut microbiota, which influences the development of obesity and associated diseases.
- Amandine Everard
- , Lucie Geurts
- & Patrice D. Cani
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Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma
Despite the treatment efficacy of combining BRAF and MEK inhibitors, a third of BRAF-mutant metastatic melanoma patients treated with this therapy progress within 6 months. Here, the authors sequence tumours from patients with BRAFV600-mutant melanoma metastases and identify mutations that confer resistance to combination therapy.
- Georgina V. Long
- , Carina Fung
- & Helen Rizos
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Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice
Hereditary hypertrophic cardiomyopathy (HCM) is caused by mutations in cardiomyocyte genes, such as MYBPC3. Here, the authors use virus-mediated gene therapy to correct Mycbpc3mutations in 1-day-old mice and, by administering just a single dose, prevent development of HCM over a period of 34 weeks.
- Giulia Mearini
- , Doreen Stimpel
- & Lucie Carrier
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Tolerance induction to human stem cell transplants with extension to their differentiated progeny
Immunosuppression has been shown to induce tolerance to transplanted stem cells, but differentiation of these cells may trigger immune rejection later on. Here, Lui et al. show that a short-term immunosuppression regimen confers long-term tolerance to stem cells and their differentiated progeny.
- Kathy O. Lui
- , Duncan Howie
- & Herman Waldmann
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A chemo-centric view of human health and disease
Forecasting unwanted interactions between drugs and chemicals in human body is an important but yet unmet need. Here the authors build networks that can predict comorbidities and drug side effects, by analysing the existing database that compiles effects of drugs and chemicals on human conditions.
- Miquel Duran-Frigola
- , David Rossell
- & Patrick Aloy
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Integrated Omic analysis of lung cancer reveals metabolism proteome signatures with prognostic impact
Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are the two major subtypes of lung cancer. Here the authors integrate omic data sets, including gene copy number, mRNA expression and proteomics, to identify subtype-specific molecular signatures and candidate drivers linked to ADC and SCC.
- Lei Li
- , Yuhong Wei
- & Michael F. Moran
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| Open AccessContrasting benefits of different artemisinin combination therapies as first-line malaria treatments using model-based cost-effectiveness analysis
Several drug combinations with different properties are used for malaria treatment. Here, Okell et al. use a mathematical model to simulate malaria transmission and treatment with two drug combinations in Africa, and find that locally optimized policies can be highly cost effective for reducing malaria burden.
- Lucy C. Okell
- , Matthew Cairns
- & Azra C. Ghani
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Dynamic analyses of alternative polyadenylation from RNA-seq reveal a 3′-UTR landscape across seven tumour types
Alternative polyadenylation (APA) has been implicated in diverse physiological and pathological conditions including cancer. The authors present a new algorithm, DaPars, for APA analysis using available RNA-seq data and suggest CstF64 as a master regulator of 3′-UTR shortening across multiple tumour types.
- Zheng Xia
- , Lawrence A. Donehower
- & Wei Li
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Redox-responsive branched-bottlebrush polymers for in vivo MRI and fluorescence imaging
Multimodal and stimuli-responsive imaging agents can yield more biological information than more typical single-mode or inert imaging probes. Here, the authors have made a dual-modal MRI-fluorescence probe and demonstrate its ability to image redox status in vivo.
- Molly A. Sowers
- , Jessica R. McCombs
- & Jeremiah A. Johnson
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A long Stokes shift red fluorescent Ca2+ indicator protein for two-photon and ratiometric imaging
Current calcium-sensitive probes based on red fluorescent proteins are unsuitable for two-photon excitation at the near-infrared wavelengths commonly used for green fluorescent probes. Wu et al. use a structure-guided approach to engineer a red fluorescent probe with optimal two-photon excitation at these wavelengths.
- Jiahui Wu
- , Ahmed S. Abdelfattah
- & Robert E. Campbell
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Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER
Reduced expression of DICER—responsible for the processing of microRNA precursors—was previously linked to poor clinical outcomes in cancer patients. Here, the authors uncover an epigenetic mechanism by which hypoxia suppresses DICER expression and deregulates the miR-200-Zeb1 circuit in breast cancer to promote the tumour phenotype.
- Twan van den Beucken
- , Elizabeth Koch
- & Bradly G. Wouters
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A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease
Mitochondrial dysfunction is associated with a number of neurodegenerative diseases. Szelechowski et al.take advantage of a viral protein that suppresses apoptosis in neurons to isolate a peptide that protects mitochondria and reduces neuronal cell death in a mouse model of Parkinson’s disease.
- Marion Szelechowski
- , Alexandre Bétourné
- & Daniel Gonzalez-Dunia
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| Open AccessGraphene-based carbon-layered electrode array technology for neural imaging and optogenetic applications
Monitoring neuronal activity in the rodent in vivobrain is commonly done using micro-electrode arrays but these devices are not normally compatible with optical technologies. Here the authors design a transparent and flexible electrode array based on graphene that allows them to combine electrophysiological recordings with optogenetic and imaging experiments.
- Dong-Wook Park
- , Amelia A. Schendel
- & Justin C. Williams
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Transparent and flexible low noise graphene electrodes for simultaneous electrophysiology and neuroimaging
Monitoring neuronal activity of large populations of neurons at high-temporal and spatial resolution is important to understand neurophysiology but requires improved tools and methods. Here the authors develop a transparent and flexible electrode based on graphene that allows them to combine electrophysiological recordings with calcium imaging.
- Duygu Kuzum
- , Hajime Takano
- & Brian Litt
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| Open AccessFunctional ultrasound imaging of intrinsic connectivity in the living rat brain with high spatiotemporal resolution
Functional connectivity of brain networks is poorly understood, in part, due to limited imaging approaches. Here, the authors use ultrasound imaging to study functional connectivity in the adult rat brain in vivo, allowing for the identification of highly contrasted intrinsic connectivity patterns.
- Bruno-Félix Osmanski
- , Sophie Pezet
- & Mickael Tanter
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Steroid hormone signalling links reproduction to lifespan in dietary-restricted Caenorhabditis elegans
Dietary restriction increases the lifespan of many species, but often at the cost of reduced fertility. Here, Thondamal et al. show that the dietary restriction-mediated increase in lifespan in Caenorhabditis elegansdepends on the production of a steroid hormone and its inhibition of germline plasticity.
- Manjunatha Thondamal
- , Michael Witting
- & Hugo Aguilaniu
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Respiratory transmission of an avian H3N8 influenza virus isolated from a harbour seal
Avian influenza viruses constantly threaten human health as evidenced by the outbreaks of human H7N9 infections. Here, Karlsson et al. show that an avian H3N8 virus isolated from harbour seals has the potential to infect, cause disease and transmit in mammalian models of influenza virus infection.
- Erik A. Karlsson
- , Hon S. Ip
- & Stacey Schultz-Cherry
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Scalable high-density peptide arrays for comprehensive health monitoring
Health monitoring based on measuring circulating antibodies may enable the presymptomatic detection of diseases. Here, the authors report a large-scale peptide array platform that allows for a detection of the profile of circulating antibodies associated with cancers and infectious diseases.
- Joseph Barten Legutki
- , Zhan-Gong Zhao
- & Phillip Stafford
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| Open AccessEnergy landscape and dynamics of brain activity during human bistable perception
Bistable visual perception requires changes in brain activity between different cortical areas. Here, Watanabe et al.demonstrate dynamic patterns of brain activity during bistable visual perception, which link behavioural variability and anatomical individual differences in focal brain regions.
- Takamitsu Watanabe
- , Naoki Masuda
- & Geraint Rees