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Article
| Open AccessA chemogenetic approach for dopamine imaging with tunable sensitivity
Dopamine regulates multiple brain functions through coexisting tonic and phasic release modalities. Here, the authors describe an approach for monitoring tonic and phasic dopamine release simultaneously via on-demand chemogenetic tuning of a dopamine sensor.
- Marie A. Labouesse
- , Maria Wilhelm
- & Tommaso Patriarchi
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Article
| Open AccessPAM-flexible Engineered FnCas9 variants for robust and ultra-precise genome editing and diagnostics
Francisella novicida Cas9 (FnCas9) has low cellular editing ability which limits its therapeutic utilities. Here, the authors rationally engineer the protein to develop enhanced FnCas9 (enFnCas9) variants with high on-target editing efficiency, high precision, broadened target range, and flexible base editing outcomes.
- Sundaram Acharya
- , Asgar Hussain Ansari
- & Debojyoti Chakraborty
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Article
| Open AccessCD4+ T cells display a spectrum of recall dynamics during re-infection with malaria parasites
CD4+ T cells are known to be important in Plasmodium infection. Here the authors use mouse models to track antigen-experienced TCR transgenic and polyclonal CD4+ T cells during Plasmodium re-infection, and show different T cell phenotypes and varied responses in different areas of the spleen.
- Hyun Jae Lee
- , Marcela L. Moreira
- & Ashraful Haque
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Article
| Open AccessCapTrap-seq: a platform-agnostic and quantitative approach for high-fidelity full-length RNA sequencing
Long-read RNA sequencing has the potential to support exhaustive annotation of eukaryotic genomes, but reliable end-to-end sequencing is still challenging. Here the authors report a method called CapTrap-seq which combines the cap-trapping strategy with oligo(dT) priming for precise full-length transcript detection.
- Sílvia Carbonell-Sala
- , Tamara Perteghella
- & Roderic Guigó
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Article
| Open AccessDistributable, metabolic PET reporting of tuberculosis
Current methods for detection of tuberculosis rely mostly on bacterial culture from sputum. Here, the authors provide preclinical evidence that a positron-emitting mimic of the disaccharide trehalose ([18F]FDT) can be used as a radiotracer for the imaging of tuberculosis-associated lesions and monitoring the effects of treatment.
- R. M. Naseer Khan
- , Yong-Mo Ahn
- & Benjamin G. Davis
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Article
| Open AccessTracking single hiPSC-derived cardiomyocyte contractile function using CONTRAX an efficient pipeline for traction force measurement
Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) are powerful in vitro models. Here the authors report CONTRAX, an open-access, versatile, and streamlined pipeline for quantitative tracking of the contractile dynamics of single hiPSC-CMs over time at increased throughput.
- Gaspard Pardon
- , Alison S. Vander Roest
- & Beth L. Pruitt
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Article
| Open AccessDivergent landscapes of A-to-I editing in postmortem and living human brain
Adenosine-to-inosine editing is a form of RNA modification observed in the human brain transcriptome. Here the authors question the accuracy of utilizing postmortem samples to reflect the RNA biology of living brains. This is due to significant differences in adenosine-to-inosine editing between living and postmortem brain tissues, with most sites exhibiting higher editing levels postmortem.
- Miguel Rodriguez de los Santos
- , Brian H. Kopell
- & Michael S. Breen
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Article
| Open AccessImputation of label-free quantitative mass spectrometry-based proteomics data using self-supervised deep learning
Imputation in mass spectrometry-based proteomics is a recurrent step of importance for downstream analysis. Here, the authors offer an extensive comparison workflow of 27 established with three new scalable, fast and performant methods from deep learning for large and high-dimensional data.
- Henry Webel
- , Lili Niu
- & Simon Rasmussen
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Article
| Open AccessDevelopment of a genetically encoded sensor for probing endogenous nociceptin opioid peptide release
Nociceptin is an opioid peptide regulating important brain functions, including motivation and 2stress responses. Here, the authors develop and validate a genetically encoded sensor as a tool for high-resolution detection of endogenous nociceptin in living animals.
- Xuehan Zhou
- , Carrie Stine
- & Tommaso Patriarchi
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Article
| Open AccessAutomated neuronal reconstruction with super-multicolour Tetbow labelling and threshold-based clustering of colour hues
Mapping of neuronal circuitry is challenging, particularly when neurons are densely packed. Here, the authors show stochastic multicolour labelling of neurons with seven fluorescent proteins. They also present an automated neurite reconstruction pipeline based on unsupervised clustering of colour information.
- Marcus N. Leiwe
- , Satoshi Fujimoto
- & Takeshi Imai
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Article
| Open AccessMapping fast DNA polymerase exchange during replication
DNA polymerase engages with DNA in various ways during replication. Using mechanical DNA manipulation and single-molecule fluorescence the authors show that replication is dynamic. Bursts of polymerase activity interspersed with protein exchanges and a memory effect can be observed, during replication.
- Longfu Xu
- , Matthew T. J. Halma
- & Gijs J. L. Wuite
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Article
| Open AccessLong-term balancing selection for pathogen resistance maintains trans-species polymorphisms in a planktonic crustacean
Trans-species polymorphisms (TSP) in disease loci are thought to be caused by long-term host-parasite coevolution. Here, the authors identify consistent TSPs across three species of Daphnia and find several genes related to immunity function for resistance to a virulent bacterial pathogen.
- Luca Cornetti
- , Peter D. Fields
- & Dieter Ebert
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Article
| Open AccessRPLP1 restricts HIV-1 transcription by disrupting C/EBPβ binding to the LTR
Here, employing proteomics profiling, the authors identify RPLP1 to be highly expressed in long-term non-progressors of HIV-1 infection. Functional validation shows that RPLP1 inhibits transcription of HIV-1 group M subtype B strains by blocking C/EBPβ binding sites, while RPLP1 knock-down promotes HIV-1 reactivation.
- Weijing Yang
- , Hong Wang
- & Wenyan Zhang
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Article
| Open AccessATP biosensor reveals microbial energetic dynamics and facilitates bioproduction
ATP dynamics influence bioproduction yet are largely unexplored in this context. Here, authors unravel ATP dynamics across various conditions, identify carbon sources which boost ATP levels and bioproduction, and uncover metabolic bottlenecks, shedding light on how ATP dynamics can be used to enhance bioproduction.
- Xinyue Mu
- , Trent D. Evans
- & Fuzhong Zhang
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Article
| Open AccessProbing the structure of water in individual living cells
Here the authors report a Raman scattering technique to measure vibrational spectrum of water inside living cells. A consistent population (~3%) of non-bulk-like water is seen, exhibiting a more disordered structure with a weakened hydrogen-bonded network.
- Xiaoqi Lang
- , Lixue Shi
- & Wei Min
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Article
| Open AccessGliovascular transcriptional perturbations in Alzheimer’s disease reveal molecular mechanisms of blood brain barrier dysfunction
Systematic studies are needed to discover molecular determinants of blood brain barrier dysfunction in Alzheimer’s disease. This study identifies perturbed pericytic SMAD3-astrocytic VEGFA interactions as a potential driver of this dysfunction.
- Özkan İş
- , Xue Wang
- & Nilüfer Ertekin-Taner
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Article
| Open AccessTherapy-induced secretion of spliceosomal components mediates pro-survival crosstalk between ovarian cancer cells
Ovarian cancers frequently develop resistance to therapy. Here, using transcriptomics, proteomics, and preclinical models to analyse paired ascitic fluids before and after chemotherapy in ovarian cancer patients, the authors discover that extracellular secretion and spliceosomal components contribute to therapy resistance, enhancing the DNA damage response in recipient cancer cells.
- Victoria O. Shender
- , Ksenia S. Anufrieva
- & Vadim M. Govorun
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Article
| Open AccessA robust model for cell type-specific interindividual variation in single-cell RNA sequencing data
Single-cell RNA sequencing (scRNA-seq) is widely used to characterize cell types based on their average gene expression profiles, however most studies do not consider cell type-specific variation across individuals. Here the authors introduce a model to study cell type-specificity of inter-individual variation in scRNA-seq data and show that it can identify biologically meaningful signals missed by conventional differential expression tests.
- Minhui Chen
- & Andy Dahl
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Article
| Open AccessLight-evoked deformations in rod photoreceptors, pigment epithelium and subretinal space revealed by prolonged and multilayered optoretinography
Optoretinography-based detection of phototransduction and cell deformations in the retina has been mostly centered on photoreceptors. Here, the authors use prolonged and multilayered optoretinography to study light-evoked deformations in rod photoreceptors, retinal pigment epithelium, and subretinal space.
- Bingyao Tan
- , Huakun Li
- & Tong Ling
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Article
| Open AccessDigital telomere measurement by long-read sequencing distinguishes healthy aging from disease
Here, the authors present digital telomere measurement, a high-throughput, quantitative approach for measuring full-length telomeres from long-read sequencing data at chromosome and base pair resolution. This digital telomere measurement can distinguish healthy aging from genetic telomere phenotypes.
- Santiago E. Sanchez
- , Yuchao Gu
- & Steven E. Artandi
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Article
| Open AccessEnhanced eMAGE applied to identify genetic factors of nuclear hormone receptor dysfunction via combinatorial gene editing
Technologies that generate precise combinatorial genome modifications are well suited to dissect the polygenic basis of complex phenotypes and engineer synthetic genomes. Here the authors systematically optimize eMAGE for enhanced editing efficiency and editing distance and apply these advances to identify genetic factors of nuclear hormone dysfunction.
- Peter N. Ciaccia
- , Zhuobin Liang
- & Farren J. Isaacs
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Article
| Open AccessEpistasis mediates the evolution of the receptor binding mode in recent human H3N2 hemagglutinin
The receptor binding mode of recent human H3N2 hemagglutinin has evolved due to mutations G186D and D190N, which epistatically interact and co-emerged in clades 3C.2a1b.1a and 3C.2a1b.2a2.
- Ruipeng Lei
- , Weiwen Liang
- & Nicholas C. Wu
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Article
| Open AccessStructural basis of S-adenosylmethionine-dependent allosteric transition from active to inactive states in methylenetetrahydrofolate reductase
Here, the authors present the structure of inactive methylenetetrahydrofolate reductase, revealing linker-mediated allostery coupled with dual SAM binding and revealing distinct domain rearrangements.
- Kazuhiro Yamada
- , Johnny Mendoza
- & Markos Koutmos
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Perspective
| Open AccessRoadblocks confronting widespread dissemination and deployment of Organs on Chips
Organ on Chip platforms hold significant promise as alternatives to traditional animal models or cell cultures. In this Perspective, the authors examine the barriers that prevent widespread dissemination and deployment of these systems.
- Charles G. Alver
- , Emma Drabbe
- & Ashutosh Agarwal
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Article
| Open AccessChip collection of hepatocellular carcinoma based on O2 heterogeneity from patient tissue
Hepatocellular carcinoma is the most common type of primary liver cancer. Here the authors show an oxygen gradient chip that separates aggressive hepatocellular carcinoma cells from a heterogeneous tumor mass, mirroring the conditions of the portal vein, hepatic artery, and liver.
- Sewoom Baek
- , Hyun-Su Ha
- & Hak-Joon Sung
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Article
| Open AccessA versatile automated pipeline for quantifying virus infectivity by label-free light microscopy and artificial intelligence
In this study, the authors report a high-throughput screening pipeline that is based on light microscopy and machine learning to quantify cytopathic effect induced by viral infection and that can be applied to clinical samples and laboratory diagnostics.
- Anthony Petkidis
- , Vardan Andriasyan
- & Urs F. Greber
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Article
| Open AccessScanless two-photon voltage imaging
Detection of membrane potential changes using voltage indicators typically requires fast imaging rates and highly sensitive imaging methods. Here, the authors introduce scanless two-photon imaging, an approach which enables high signal to noise ratio voltage recordings at kilohertz rates, from multiple neurons simultaneously, both in vitro and in vivo.
- Ruth R. Sims
- , Imane Bendifallah
- & Valentina Emiliani
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Article
| Open AccessTopological regression as an interpretable and efficient tool for quantitative structure-activity relationship modeling
Quantitative structure-activity relationships (QSAR) models are widely used in drug discovery, but have limitations in their interpretability and accuracy near activity cliffs. Here the authors use a topological regression framework to increase QSAR interpretability and efficiency.
- Ruibo Zhang
- , Daniel Nolte
- & Ranadip Pal
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Article
| Open AccessDissecting tumor microenvironment from spatially resolved transcriptomics data by heterogeneous graph learning
Dissecting the relations between cells, genes, and histological regions in the tumor microenvironment (TME) remains challenging. Here, the authors develop stKeep, a heterogeneous graph learning method that integrates multimodal data and gene-gene interactions to identify cell states and composition in the TME from spatial transcriptomics.
- Chunman Zuo
- , Junjie Xia
- & Luonan Chen
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Article
| Open AccessGel-assisted mass spectrometry imaging enables sub-micrometer spatial lipidomics
Mass spectrometry imaging (MSI) is often limited by low spatial resolution. Here, the authors propose Gel-Assisted Mass Spectrometry Imaging (GAMSI), which enhances the spatial resolution of MALDI-MSI monitoring of lipids and proteins to the sub-micrometre level without changing existing hardware setups.
- Yat Ho Chan
- , Koralege C. Pathmasiri
- & Ruixuan Gao
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Article
| Open AccessTau follows principal axes of functional and structural brain organization in Alzheimer’s disease
In Alzheimer’s disease, the role of connectivity in facilitating pathology accumulation remains unclear. Using in-vivo neuroimaging, the authors show that tau and reactive microglia follow connectome gradients, underlying cognitive decline.
- Julie Ottoy
- , Min Su Kang
- & Maged Goubran
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Article
| Open AccessA probe for NIR-II imaging and multimodal analysis of early Alzheimer’s disease by targeting CTGF
Here the authors report an NIR-II gold probe for identification of early-stage AD. The probe enables non-invasive NIR-II imaging of elevated CTGF in brains of early AD mice and multimodally identifying AD patients’ brain sections before obvious Aβ deposition.
- Cao Lu
- , Cong Meng
- & Xueyun Gao
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Article
| Open AccessdescSPIM: an affordable and easy-to-build light-sheet microscope optimized for tissue clearing techniques
Poor access to suitable light-sheet microscopes remains a big obstacle for many end-users in biomedical research. Here, the authors present descSPIM, a low-cost, low-expertise light-sheet microscope for routine 3D imaging of cleared samples.
- Kohei Otomo
- , Takaki Omura
- & Etsuo A. Susaki
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Article
| Open AccessCoHIT: a one-pot ultrasensitive ERA-CRISPR system for detecting multiple same-site indels
Genetic testing is crucial for precision cancer medicine. Here, the authors develop a one-pot ERA-CRISPR assay to detect variable same-site indels, using an engineered AsCas12a variant with improved mismatch tolerance and broadened PAM scope.
- Yin Liu
- , Xinyi Liu
- & Fuling Zhou
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Article
| Open AccessCRIMP: a CRISPR/Cas9 insertional mutagenesis protocol and toolkit
Site-directed insertion is a powerful approach for generating mutant lines but, historically, technically challenging. Here, the authors demonstrate CRIMP, an optimised protocol and universal toolkit (CRIMPkit), to greatly improve the efficacy of generating and studying mutant lines.
- Lee B. Miles
- , Vanessa Calcinotto
- & Robert J. Bryson-Richardson
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Article
| Open AccessAxial de-scanning using remote focusing in the detection arm of light-sheet microscopy
The authors propose a method for de-scanning the axial focus movement in the detection arm of a fluorescence microscope, enabling aberration-free, multi-color, volumetric imaging. They acquire dual-colour image stacks with an axial range of 70 μm and camera-limited acquisition speed.
- Hassan Dibaji
- , Ali Kazemi Nasaban Shotorban
- & Tonmoy Chakraborty
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Article
| Open AccessRed2Flpe-SCON: a versatile, multicolor strategy for generating mosaic conditional knockout mice
Inducible genetic mosaics can provide information about cellular lineages that are otherwise difficult to obtain. Here the authors report a mosaic knockout system called Red2Flpe-SCON, which allows lineage tracing of wild-type and mutant cells using a multicolour fluorescent reporter in mice.
- Szu-Hsien Sam Wu
- , Somi Kim
- & Bon-Kyoung Koo
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Article
| Open AccessOptimizing the design of spatial genomic studies
New technologies assay tissue slices for cell locations and molecular markers, aiding in the study of tissue cellular organisation. Here, authors develop an experimental design method to improve the cost-efficiency of spatial genomics experiments by iteratively selecting the most informative tissue slices.
- Andrew Jones
- , Diana Cai
- & Barbara E. Engelhardt
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Article
| Open AccessCosmic kidney disease: an integrated pan-omic, physiological and morphological study into spaceflight-induced renal dysfunction
Siew et al. using multi-omic, physiological & imaging approaches have demonstrated that spaceflight causes kidney remodelling, suggesting a contribution to kidney stone formation, & that space radiation causes kidney damage & early signs of dysfunction.
- Keith Siew
- , Kevin A. Nestler
- & Stephen B. Walsh
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Article
| Open AccessDirect RNA sequencing of astronaut blood reveals spaceflight-associated m6A increases and hematopoietic transcriptional responses
Here the authors explore the role of chemical modifications within RNA molecules in spaceflight response, observing increased m6A mRNA modifications immediately post-spaceflight in gene markers associated with stress response.
- Kirill Grigorev
- , Theodore M. Nelson
- & Christopher E. Mason
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Article
| Open AccessTranscranial focused ultrasound to V5 enhances human visual motion brain-computer interface by modulating feature-based attention
Transcranial focused ultrasound (tFUS) is a non-invasive brain modulation technology with high spatiotemporal specificity. Here, authors found tFUS can significantly enhance a brain-computer interface speller by delivering low-intensity tFUS to visual cortex during the task in naïve human subjects.
- Joshua Kosnoff
- , Kai Yu
- & Bin He
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Article
| Open AccessEngineering viral vectors for acoustically targeted gene delivery
Targeted gene delivery to the brain is a critical tool for neuroscience research and has significant potential to treat human disease. Here the authors engineer the protein shell of a common gene therapy vector for enhanced efficiency and specificity of brain delivery in ultrasound-targeted brain regions.
- Hongyi R. Li
- , Manwal Harb
- & Jerzy O. Szablowski
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Article
| Open AccessExploring plant-derived phytochrome chaperone proteins for light-switchable transcriptional regulation in mammals
Synthetic biology applications require finely tuned gene expression, often mediated by synthetic transcription factors. Here the authors validate two plant-derived proteins, FHY1 and FHL, acting as transactivators in mammalian cells for orthogonal, modular, and tunable control of gene transcription by forming a photosensing transcriptional regulation complex with PhyA.
- Deqiang Kong
- , Yang Zhou
- & Haifeng Ye
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Article
| Open AccessDevelopment of deaminase-free T-to-S base editor and C-to-G base editor by engineered human uracil DNA glycosylase
Efficient base editors for direct thymine (T) editing are highly desirable. Here, authors develop two deaminase-free glycosylase-based base editors for direct T editing (gTBE) and C editing (gCBE) by rounds of structure-informed mutagenesis on human DNA glycosylase UNG and further engineering.
- Huawei Tong
- , Haoqiang Wang
- & Hui Yang
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Article
| Open AccessDepth-enhanced high-throughput microscopy by compact PSF engineering
Implementing point spread function (PSF) engineering in high-throughput microscopy has proved challenging. Here, the authors propose a compact PSF engineering approach, which allows for enhanced depth of field and for the recovery of 3D information using single snapshots.
- Nadav Opatovski
- , Elias Nehme
- & Yoav Shechtman
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Article
| Open AccessEvolution of connectivity architecture in the Drosophila mushroom body
Brain evolution at the cellular level is understudied. Here, the authors compare olfactory circuits from three Drosophila species, finding species-specific connectivity patterns associated with food odours and suggesting that more connectivity may be related to learning performance.
- Kaitlyn Elizabeth Ellis
- , Sven Bervoets
- & Sophie Jeanne Cécile Caron
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Article
| Open AccessOptimizing cell therapy by sorting cells with high extracellular vesicle secretion
Extracellular vesicles have been exploited as potential therapeutic agents. Here, the authors apply a nanovial technology to select sub-populations of cells that secrete high levels of extracellular vesicles, leading to improved therapeutic efficacy when delivered in vivo.
- Doyeon Koo
- , Xiao Cheng
- & Dino Di Carlo
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Article
| Open AccessMonths-long tracking of neuronal ensembles spanning multiple brain areas with Ultra-Flexible Tentacle Electrodes
Techniques to perform long-term recordings of brain activity from different areas are key to investigating many processes. Here, the authors introduce a tentacular implant with many independent fibers to track neuronal ensembles spanning multiple brain areas for months.
- Tansel Baran Yasar
- , Peter Gombkoto
- & Mehmet Fatih Yanik
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Article
| Open AccessSupramolecular assembly activated single-molecule phosphorescence resonance energy transfer for near-infrared targeted cell imaging
Phosphorescence resonance energy transfer systems have potential in light-harvesting and bioimaging, but host-guest systems are rarely explored. Here, the authors report the development of a macrocyclic host-guest system for targeted cell imaging.
- Xiaolu Zhou
- , Xue Bai
- & Yu Liu
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