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| Open AccessPolycomb-mediated silencing of miR-8 is required for maintenance of intestinal stemness in Drosophila melanogaster
Intestinal physiology requires a balance between stem cell self-renewal and differentiation. Here, the authors show that this balance is regulated epigenetically by a dynamic relationship between the evolutionarily conserved PRC2, miR-8 and Notch signaling.
- Zoe Veneti
- , Virginia Fasoulaki
- & Aristides G. Eliopoulos
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Article
| Open AccessDistinct neurochemical influences on fMRI response polarity in the striatum
The relationship between striatal vascular and neural activity is not fully understood. Here the authors found neuronal activity inadequately explains striatal hemodynamic polarity, challenging classic fMRI interpretations.
- Domenic H. Cerri
- , Daniel L. Albaugh
- & Yen-Yu Ian Shih
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Article
| Open AccessCryo-EM structure of cell-free synthesized human histamine 2 receptor/Gs complex in nanodisc environment
The study describes the molecular structure of the human histamine 2 receptor in active conformation and in complex with Gs heterotrimer, synthesized in a cell-free system and co-translationally inserted into preformed nanodiscs.
- Zoe Köck
- , Kilian Schnelle
- & Frank Bernhard
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Article
| Open AccessMirror-image ligand discovery enabled by single-shot fast-flow synthesis of D-proteins
Mirror-image phage display has the potential for high-throughput generation of biologically stable macrocyclic D-peptide binders but is hindered by the optimization required for D-protein chemical synthesis. Here, the authors report a general mirror-image phage display pipeline based on automated flow peptide synthesis and use it to prepare and characterize 12 L/D-protein pairs.
- Alex J. Callahan
- , Satish Gandhesiri
- & Bradley L. Pentelute
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Article
| Open AccessscCircle-seq unveils the diversity and complexity of extrachromosomal circular DNAs in single cells
Extrachromosomal circular DNAs (eccDNAs) affect gene expression and tumour progression. Here, the authors report a method, scCircle-seq, for eccDNA profiling in single cells, demonstrating the stochasticity, cell type specificity, and dynamics of eccDNAs in cell lines and primary tumour samples.
- Jinxin Phaedo Chen
- , Constantin Diekmann
- & Nicola Crosetto
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Article
| Open AccessMeasuring sub-nanometer undulations at microsecond temporal resolution with metal- and graphene-induced energy transfer spectroscopy
Studying the fluctuations of biological membranes with high resolution is challenging. Here, the authors combine metal- and graphene-induced energy transfer (MIET/GIET) with fluorescence correlation spectroscopy (FCS) to monitor such fluctuations with nanometer and microsecond resolution.
- Tao Chen
- , Narain Karedla
- & Jörg Enderlein
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Article
| Open AccessAutomatic data-driven design and 3D printing of custom ocular prostheses
Manual processes to produce ocular prostheses are time-consuming and yield varying quality. Here, authors present an automatic digital end-to-end process for custom ocular prostheses. It creates shape and appearance from image data of an OCT device and produces them using a full-colour 3D printer.
- Johann Reinhard
- , Philipp Urban
- & Mandeep S. Sagoo
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Article
| Open AccessEngineering self-deliverable ribonucleoproteins for genome editing in the brain
The delivery of CRISPR RNPs has potential advantages over other genome editing approaches, including reduced off-target editing and reduced immunogenicity. Here the authors report self-deliverable Cas9 RNPs capable of robustly editing cultured cells in vitro and the mouse brain upon direct injections.
- Kai Chen
- , Elizabeth C. Stahl
- & Jennifer A. Doudna
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Article
| Open AccessDeciphering the mechanism of glutaredoxin-catalyzed roGFP2 redox sensing reveals a ternary complex with glutathione for protein disulfide reduction
Fusion proteins between roGFP2 and glutaredoxins are used for intracellular redox measurements. Here, the authors determined all rate constants of the reaction cycle for roGFP2 measurements and identified an alternative glutaredoxin mechanism.
- Fabian Geissel
- , Lukas Lang
- & Marcel Deponte
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Article
| Open AccessNucleocapsid protein-specific monoclonal antibodies protect mice against Crimean-Congo hemorrhagic fever virus
There are limited treatment options for infection with Crimean-Congo hemorrhagic fever virus in humans. Here, the authors show that a monoclonal antibody targeting the highly conserved viral nucleocapsid protein provides protective effects in a mouse model of infection.
- Aura R. Garrison
- , Vanessa Moresco
- & Joseph W. Golden
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Article
| Open AccessMarShie: a clearing protocol for 3D analysis of single cells throughout the bone marrow at subcellular resolution
Three-dimensional analysis of the intact bone marrow within whole long bones remains very challenging. Here, the authors present a method that stabilizes the marrow and provides subcellular resolution of fluorescent signals throughout the murine femur.
- Till Fabian Mertens
- , Alina Tabea Liebheit
- & Anja Erika Hauser
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Article
| Open AccessSEMORE: SEgmentation and MORphological fingErprinting by machine learning automates super-resolution data analysis
There is a lack of universal tools to analyse protein assemblies and quantify underlying structures in single-molecule localization microscopy. Here, the authors present SEMORE, a semi-automatic machine learning framework for system- and input-dependent analysis of super-resolution data.
- Steen W. B. Bender
- , Marcus W. Dreisler
- & Nikos S. Hatzakis
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Article
| Open AccessT-DOpE probes reveal sensitivity of hippocampal oscillations to cannabinoids in behaving mice
Neural activity is regulated by synapse-neuromodulator interactions, necessitating optoelectro-pharmacological investigations. Here, authors implement their multi-modal probe to show focal infusion of synthetic cannabinoid disrupts CA1 oscillations.
- Jongwoon Kim
- , Hengji Huang
- & Xiaoting Jia
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Article
| Open AccessPhage-assisted evolution of highly active cytosine base editors with enhanced selectivity and minimal sequence context preference
Existing TadA-derived CBEs exhibit residual A•T-to-G•C editing activity and suffer from lower activity at several sequence contexts and with non-SpCas9 targeting domains. Here, the authors use phage-assisted evolution to evolve CBE6 variants that address these limitations.
- Emily Zhang
- , Monica E. Neugebauer
- & David R. Liu
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Article
| Open AccessSingle-molecule RNA sizing enables quantitative analysis of alternative transcription termination
The development of RNA technologies demands accurate assessment of transcript size and heterogeneity. Here, authors report a nanopore-based approach to study full-length RNA transcripts at the single-molecule level, identify premature transcription termination and study rolling-circle transcription.
- Gerardo Patiño-Guillén
- , Jovan Pešović
- & Ulrich Felix Keyser
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Article
| Open AccessVirtual histological staining of unlabeled autopsy tissue
Conventional staining of post-mortem samples can be affected by several factors, including tissue autolysis. Here, the authors demonstrate a virtual staining tool using a trained neural network to turn autofluorescence images of label-free autopsy tissue into brightfield equivalent images.
- Yuzhu Li
- , Nir Pillar
- & Aydogan Ozcan
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Article
| Open AccessMotility of an autonomous protein-based artificial motor that operates via a burnt-bridge principle
Inspired by biology, great progress has been made in creating artificial molecular motors. Here the authors report the synthesis and characterization of the Lawnmower, an autonomous, protein-based artificial molecular motor and show their design is capable of track-guided motion.
- Chapin S. Korosec
- , Ivan N. Unksov
- & Nancy R. Forde
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Article
| Open AccessProtein design using structure-based residue preferences
Recent protein design methods rely on large neural networks, yet it is unclear which dependencies are critical for determining function. Here, authors show that learning the per residue mutation preferences, without considering interactions, enables design of functional and diverse protein variants.
- David Ding
- , Ada Y. Shaw
- & Debora S. Marks
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Article
| Open AccessBlack phosphorus boosts wet-tissue adhesion of composite patches by enhancing water absorption and mechanical properties
The utility of wet-tissue adhesives has been impeded by the suboptimal adhesive strength. Here the authors report a composite patch integrated with BP nanosheets that improve the wet-tissue adhesion by enhancing the water absorption and mechanical properties of the patch and demonstrate the uses of the patch in hemostasis, physical-activity monitoring and tumour-recurrence prevention.
- Yuanchi Zhang
- , Cairong Li
- & Yuxiao Lai
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Article
| Open AccessMulti-molecular hyperspectral PRM-SRS microscopy
Spatial imaging methods in lipid research can disrupt tissue integrity and can have limited spatial and spectral resolution. Here, the authors present an SRS-based hyperspectral imaging platform to visualise lipids and lipoproteins in a variety of tissues and animal species.
- Wenxu Zhang
- , Yajuan Li
- & Lingyan Shi
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Article
| Open AccessEfficient encoding of large antigenic spaces by epitope prioritization with Dolphyn
Profiling antibody responses to vast antigenic spaces has been challenging using programmable phage display (PhIP-Seq). Here, authors develop a methodology for compressing large proteomic spaces and have discovered human antibodies targeting gut bacteria-infecting phages.
- Anna-Maria Liebhoff
- , Thiagarajan Venkataraman
- & H. Benjamin Larman
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Article
| Open AccessOpen-source microscope add-on for structured illumination microscopy
Researchers developed an open-hardware structured illumination microscopy add-on. This affordable upgrade provides super-resolution capabilities for normal optical microscopes. Detailed instructions enable easy reproduction to help democratize advanced microscopy.
- Mélanie T. M. Hannebelle
- , Esther Raeth
- & Georg E. Fantner
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Article
| Open AccessGenome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover
Mechanisms regulating collagen clearance may be useful for treating fibrosis. Here, the authors conducted functional genome-wide screens and found that collagen biosynthesis directly regulates collagen clearance via a noncanonical function of SEL1L.
- Michael J. Podolsky
- , Benjamin Kheyfets
- & Kamran Atabai
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Article
| Open AccessA single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution
Unlike most inflammatory fibrotic conditions, frozen shoulder is a spontaneously self-resolving human disease. Here authors study samples from frozen shoulder capsules by single cell RNA sequencing and by microculture modelling of cell-cell interactions to conclude that specific macrophage populations and their interaction with fibroblasts might promote fibrosis resolution.
- Michael T. H. Ng
- , Rowie Borst
- & Stephanie G. Dakin
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Article
| Open AccessAn ultrasensitive and broadband transparent ultrasound transducer for ultrasound and photoacoustic imaging in-vivo
Transparent ultrasound transducers suffer from practical limitations due to acoustic impedance mismatch. By using a transparent adhesive based on silicon dioxide epoxy, the authors demonstrate a broadband, ultrasensitive transparent ultrasound transducer, advancing the possibilities of sensor fusion.
- Seonghee Cho
- , Minsu Kim
- & Chulhong Kim
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Article
| Open AccessArticular surface interactions distinguish dinosaurian locomotor joint poses
Criteria for evaluating joint articulation in vertebrates are lacking. Here, the authors propose an approach for combining measurements of 3D articular overlap, symmetry, and congruence into a single metric, and apply this to examine the walking stride of Deinonychus antirrhopus.
- Armita R. Manafzadeh
- , Stephen M. Gatesy
- & Bhart-Anjan S. Bhullar
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Article
| Open AccessCompact zinc finger architecture utilizing toxin-derived cytidine deaminases for highly efficient base editing in human cells
The most recent class of base editors utilize DddAtox, a deaminase domain that can act upon double-stranded DNA. Here the authors target DddAtox fragments and a FokI-based nickase to the human CIITA gene by fusing these domains to arrays of engineered zinc fingers; they also identify a variety of DddAtox orthologues.
- Friedrich Fauser
- , Bhakti N. Kadam
- & Jeffrey C. Miller
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Article
| Open AccessModeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip
Here the authors develop perfusable inner blood-retinal barrier-specific microvascular networks with human primary retinal microvascular cells. They show that chronic diabetic stimulation leads to the generation of early hallmarks of diabetic retinopathy, including pericyte and capillary dropout, ghost vessels, and inflammation.
- Thomas L. Maurissen
- , Alena J. Spielmann
- & Héloïse Ragelle
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Article
| Open AccessOperando investigation of the synergistic effect of electric field treatment and copper for bacteria inactivation
The overuse of chemicals in our disinfection processes has warranted the development of alternatives. Here, authors use a lab-on-a-chip device to study and observe the synergistic effects of electric field treatment and copper for inactivation of bacteria with promising applications in many fields.
- Mourin Jarin
- , Ting Wang
- & Xing Xie
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Article
| Open AccessA deep-learning-based framework for identifying and localizing multiple abnormalities and assessing cardiomegaly in chest X-ray
Accurate localization of abnormalities is crucial in the interpretation of chest X-rays. Here the authors present a deep learning framework for simultaneous localization of 14 thoracic abnormalities and calculation of cardiothoracic ratio, based on large X-ray dataset with bounding boxes created via a human-in-the-loop approach.
- Weijie Fan
- , Yi Yang
- & Dong Zhang
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Article
| Open AccessPredicting proximal tubule failed repair drivers through regularized regression analysis of single cell multiomic sequencing
A profibrotic, proinflammatory kidney cell population has been identified as a driver of chronic kidney disease. Here, authors generate a human kidney single cell multiomic dataset and apply a regularised regression approach to identify transcription factors underpinning this cell population.
- Nicolas Ledru
- , Parker C. Wilson
- & Benjamin D. Humphreys
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Article
| Open AccessMesoscopic calcium imaging in a head-unrestrained male non-human primate using a lensless microscope
Current systems for imaging calcium dynamics in the brains of non-human primates require the animal’s movement to be restricted. Here, the authors demonstrate a mesoscale calcium imaging device in a freely moving non-human primate which features a 20 mm2 field of view.
- Jimin Wu
- , Yuzhi Chen
- & Jacob T. Robinson
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Article
| Open AccessEco-evolutionary dynamics of gut phageome in wild gibbons (Hoolock tianxing) with seasonal diet variations
The significance of gut phageome for wild animals with seasonal diets remains unexplored. Here, the authors use complementary metagenomics to analyze the phage-host dynamics and its implications for diet variations in wild skywalker hoolock gibbons.
- Shao-Ming Gao
- , Han-Lan Fei
- & Peng-Fei Fan
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Article
| Open AccessPick-up single-cell proteomic analysis for quantifying up to 3000 proteins in a Mammalian cell
Single-cell proteomics is of fundamental importance to capture biological heterogeneity, while limited in proteome depth. Here, the authors develop a pick-up single-cell proteomic analysis (PiSPA) workflow to achieve a deep coverage of quantifying up to 3000 protein groups in a mammalian cell.
- Yu Wang
- , Zhi-Ying Guan
- & Qun Fang
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Article
| Open AccessUsing the heme peroxidase APEX2 to probe intracellular H2O2 flux and diffusion
Previous genetically encoded H2O2 probes are based on reversible thiol oxidation. Here, a heme peroxidase is introduced as a thiol-independent H2O2 probe. APEX2 converts H2O2 into fluorescent or luminescent signals, allowing its quantification.
- Mohammad Eid
- , Uladzimir Barayeu
- & Tobias P. Dick
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Article
| Open AccessDrug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor
There is a need for effective antiviral drugs against RSV infection. Conducting an RSV repurposing screen using the ReFRAME library Sake et al. identify lonafarnib as an RSV fusion protein inhibitor, characterize its binding site within the viral protein and show its antiviral effects in a mouse model.
- Svenja M. Sake
- , Xiaoyu Zhang
- & Thomas Pietschmann
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Article
| Open AccessTrophoblast stem cell-based organoid models of the human placental barrier
The placenta is a transient organ that regulates the fetal environment, but our understanding of placental barrier function has been hampered by the lack of in vitro models. Here they develop human placental organoids that resemble the placental villus and form an intact syncytiotrophoblast barrier when cultured in a column model.
- Takeshi Hori
- , Hiroaki Okae
- & Hirokazu Kaji
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Article
| Open AccessOrthogonal LoxPsym sites allow multiplexed site-specific recombination in prokaryotic and eukaryotic hosts
Site-specific recombinases such as the Cre-LoxP system are routinely used for genome engineering in both prokaryotes and eukaryotes. Here the authors develop 63 symmetrical LoxP variants and test 1192 pairwise combinations to determine their cross-reactivity and specificity upon Cre activation.
- Charlotte Cautereels
- , Jolien Smets
- & Kevin J. Verstrepen
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Article
| Open AccessN2FXm, a method for joint nuclear and cytoplasmic volume measurements, unravels the osmo-mechanical regulation of nuclear volume in mammalian cells
Cells exert tight control over the size of their compartments in order to regulate their function. Here, nuclear fluorescence exclusion microscopy is able to measure the nuclear and cytoplasmic volumes of live cells in a high-throughput way.
- Fabrizio A. Pennacchio
- , Alessandro Poli
- & Paolo Maiuri
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Article
| Open AccessThe synthetic NLR RGA5HMA5 requires multiple interfaces within and outside the integrated domain for effector recognition
An engineered sensor NLR RGA5HMA5 carrying multiple resurfaced interfaces was generated to confer complete resistance to the rice blast fungus strains expressing the non-corresponding effector AVR-PikD, paving a way to broaden the resistance spectra of NLRs.
- Xin Zhang
- , Yang Liu
- & You-Liang Peng
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Article
| Open AccessAAV-delivered muscone-induced transgene system for treating chronic diseases in mice via inhalation
Long-term control of therapeutic transgene expression is needed. Here the authors report a muscone-induced transgene system packaged into AAVs based on a G protein-coupled murine olfactory receptor and a synthetic cAMP-responsive promoter: they show dose- and exposure-time-dependent gene expression control in mice.
- Xin Wu
- , Yuanhuan Yu
- & Haifeng Ye
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Article
| Open AccessEvolution of chemosensory tissues and cells across ecologically diverse Drosophilids
Chemosensory tissues are remarkably variable between species but the cause of this diversity is unclear. Here, the authors conduct transcriptomic analyses of chemosensory tissues from diverse Drosophila species, revealing evidence of stabilizing selection and recent species- and sex-specific changes.
- Gwénaëlle Bontonou
- , Bastien Saint-Leandre
- & J. Roman Arguello
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Article
| Open AccessIsolation and characterization of a pangolin-borne HKU4-related coronavirus that potentially infects human-DPP4-transgenic mice
Pangolins are a potential reservoir for viruses with cross-species infection potential. Here, the authors characterize a HKU4-related coronavirus isolated from pangolin and demonstrate its ability to infect human cell lines as well as its potential to infect transgenic mice expressing the human receptor DPP4.
- Luo-Yuan Xia
- , Zhen-Fei Wang
- & Wu-Chun Cao
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Article
| Open AccessShort-term periodic restricted feeding elicits metabolome-microbiome signatures with sex dimorphic persistence in primate intervention
Here, the authors show that periodic restricted feeding (PRF) in Rhesus monkeys induces lasting weight loss not directly tied to reduced calories, while altering sex-specific metabolome and microbiome composition, in turn associated with long-term benefits.
- Hagai Yanai
- , Bongsoo Park
- & Isabel Beerman
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Article
| Open AccessGeometric transformation adaptive optics (GTAO) for volumetric deep brain imaging through gradient-index lenses
The GRIN lenses widely used for deep brain functional imaging suffer from a small measurement field of view due to strong fourth-order astigmatism. Here the authors report Geometric Transformation Adaptive Optics (GTAO) that corrects field-dependent astigmatism and enables large-volume in vivo imaging of deep mouse brain through 0.5 mm GRIN lenses.
- Yuting Li
- , Zongyue Cheng
- & Meng Cui
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Article
| Open AccessTigerfish designs oligonucleotide-based in situ hybridization probes targeting intervals of highly repetitive DNA at the scale of genomes
Repetitive DNA intervals play important roles in the nucleus but are difficult to study due to their reiterated nature. Tigerfish introduces a novel computational platform for the design of interval-specific in situ hybridization probes.
- Robin Aguilar
- , Conor K. Camplisson
- & Brian J. Beliveau
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Article
| Open AccessNanoparticle enrichment mass-spectrometry proteomics identifies protein-altering variants for precise pQTL mapping
Genetic association studies with affinity proteomics face challenges when dealing with protein altering variants. Suhre et al. show that nanoparticle enrichment mass-spectrometry can distinguish between epitope effects and bona fide protein quantitative traits.
- Karsten Suhre
- , Guhan Ram Venkataraman
- & Frank Schmidt
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Article
| Open AccessMolecular-level architecture of Chlamydomonas reinhardtii’s glycoprotein-rich cell wall
Chlamydomonas reinhardtii produces a glycoprotein-rich cell wall. Using nuclear magnetic resonance and mass spectrometry approaches, this study reveals unprecedented details on its protein and carbohydrate content, and provide an atomic-level architecture model.
- Alexandre Poulhazan
- , Alexandre A. Arnold
- & Isabelle Marcotte
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Article
| Open AccessAn intranasal live-attenuated SARS-CoV-2 vaccine limits virus transmission
In this study, the authors evaluated the protective capacity of a mucosal, live-attenuated SARS-CoV-2 vaccine and show that it induces systemic and mucosal humoral immunity, protects from clinical disease symptoms, and prevents virus transmission in hamsters more efficiently than an intramuscular mRNA vaccine.
- Julia M. Adler
- , Ricardo Martin Vidal
- & Jakob Trimpert
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