Featured
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Article
| Open AccessPD-1/CD80+ small extracellular vesicles from immunocytes induce cold tumours featured with enhanced adaptive immunosuppression
Immune checkpoint inhibition is a successful form of immune therapy; however response rates vary widely among individual patients. Here authors show that circulating small extracellular vesicles might contribute to poor response to anti-PD-1 treatment by carrying PD-1 and CD80 which results in higher level of vesicular PD-L1 expression in the circulation at the expense of expression on tumour cell membranes, causing immunosuppression.
- Lin-Zhou Zhang
- , Jie-Gang Yang
- & Gang Chen
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Article
| Open AccessIntramolecular autoinhibition regulates the selectivity of PRPF40A tandem WW domains for proline-rich motifs
The specific recognition of a proline-rich motif in the intrinsically disordered region of SF1 by the PRPF40A tandem WW domains is modulated by an intramolecular autoinhibition, suggesting a general mechanism to enhance WW binding selectivity.
- Santiago Martínez-Lumbreras
- , Lena K. Träger
- & Michael Sattler
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Article
| Open AccessThe Shigella kinase effector OspG modulates host ubiquitin signaling to escape septin-cage entrapment
Here, Xian et al. use phosphoproteomics to identify that the Shigella effector OspG interacts with a regulator of Cullin-RING ubiquitin ligases to promote the ubiquitination of septins and consequent inhibition of septin cage formation.
- Wei Xian
- , Jiaqi Fu
- & Xiaoyun Liu
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Article
| Open AccessCadmium binding by the F-box domain induces p97-mediated SCF complex disassembly to activate stress response programs
The F-box domain is a conserved structural motif in ubiquitin ligases known only to bind Skp1. Here, the authors show the F-box domain is also an environmental cadmium sensor that changes conformation upon binding to disassemble the active ligase, protecting the cell from cadmium stress.
- Linda Lauinger
- , Anna Andronicos
- & Peter Kaiser
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Article
| Open AccessStructural basis and synergism of ATP and Na+ activation in bacterial K+ uptake system KtrAB
KtrAB complex is essential in K+ uptake for bacteria. Here authors illustrate the synergism of ATP and Na+ in activating K+ uptake of KtrAB from Bacillus subtilis and its gating mechanism, which may also shed light on other Na+-activated K+ channels.
- Wesley Tien Chiang
- , Yao-Kai Chang
- & Nien-Jen Hu
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Article
| Open AccessA quantitative gibberellin signaling biosensor reveals a role for gibberellins in internode specification at the shoot apical meristem
Engineering of a biosensor allows the authors to map the signaling activity of the phytohormones gibberellins (GAs) and to show that GAs orient cell division at the shoot apex to establish the organization in parallel cell files of plant stems.
- Bihai Shi
- , Amelia Felipo-Benavent
- & Teva Vernoux
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Article
| Open AccessMechanistic basis of the dynamic response of TWIK1 ionic selectivity to pH
Using computer simulations authors identify the dynamic molecular motions controlling the structural conformation of the TWIK1 ion channel, showing that its ability to transport sodium upon acidification result from the evolution of the classical potassium-selective pore.
- Franck C. Chatelain
- , Nicolas Gilbert
- & Olivier Bignucolo
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Article
| Open AccessMeCP2 binds to methylated DNA independently of phase separation and heterochromatin organisation
The heterochromatic 'condensates' may not be conserved across mammals. This study highlights the influence of host genome on nuclear architecture and challenges the hypothesis that heterochromatin and MeCP2 undergo phase separation.
- Raphaël Pantier
- , Megan Brown
- & Adrian Bird
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Article
| Open AccessIdentification of a family of species-selective complex I inhibitors as potential anthelmintics
Soil-transmitted helminths (STHs) are major pathogens. Here the authors screen 480 structural families of natural products to find compounds that kill Caenorhabditis elegans specifically when they require rhodoquinone (RQ)-dependent metabolism: they identify several classes of compounds and show some compounds kill adult STHs.
- Taylor Davie
- , Xènia Serrat
- & Andrew G. Fraser
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Article
| Open AccessPredicting vaccine effectiveness for mpox
Here, based on a systematic review and meta-analysis, the authors analyze the relationship between vaccine immunogenicity and vaccine protection against mpox and predict the durability of protection after vaccination. This helps inform the optimal vaccine deployment in a health emergency.
- Matthew T. Berry
- , Shanchita R. Khan
- & David S. Khoury
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Article
| Open AccessPhytohormone profiling in an evolutionary framework
Genomic evidence dates the origins of most phytohormones to terrestrialization or later. Here, the authors show that the biosynthesis of many compounds in green algae preceded their recruitment in phytohormone signaling and metabolism in land plants.
- Vojtěch Schmidt
- , Roman Skokan
- & Jan Petrášek
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Article
| Open AccessPrecise immunofluorescence canceling for highly multiplexed imaging to capture specific cell states
Multiplexed imaging to study cellular pathways can be hampered by lack of antibody specificity, especially when assessing signal activation. Here, the authors present Precise Emission Canceling Antibodies (PECAbs), which enable high-specificity sequential imaging and the study of signaling pathways.
- Kosuke Tomimatsu
- , Takeru Fujii
- & Yasuyuki Ohkawa
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Article
| Open AccessSpontaneous persistent activity and inactivity in vivo reveals differential cortico-entorhinal functional connectivity
Cortico-entorhinal interactions remain poorly understood. Here, the authors demonstrate that a model of interacting networks predicts spontaneous persistent activity and inactivity in the medial, but not lateral, entorhinal cortex in vivo.
- Krishna Choudhary
- , Sven Berberich
- & Mayank R. Mehta
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Article
| Open AccessRepression of developmental transcription factor networks triggers aging-associated gene expression in human glial progenitor cells
Human glial progenitor cells (hGPCs) lose mitotic competence with age. Here, the authors show that with maturation, adult hGPCs acquire a set of transcriptional repressors that actively suppress developmental gene expression.
- John N. Mariani
- , Benjamin Mansky
- & Steven A. Goldman
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Article
| Open AccessPlasma proteome profiling reveals dynamic of cholesterol marker after dual blocker therapy
Dual blockade therapy is currently being trialled for multiple tumour types, but efficacy is variable. Here, the authors use longitudinal proteomics profiling of 22 patients to develop a predictive model of therapy response.
- Jiacheng Lyu
- , Lin Bai
- & Chen Ding
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Article
| Open AccessNative N-glycome profiling of single cells and ng-level blood isolates using label-free capillary electrophoresis-mass spectrometry
Single-cell manipulation and processing techniques and improvements in mass spectrometry sensitivity make single-cell proteomic profiling feasible. This study presents a label-free approach for the characterisation of native N-glycans of single mammalian cells and ng-level blood isolates, demonstrating the potential to detect cell surface glycome changes at the single-cell level in health or disease.
- Anne-Lise Marie
- , Yunfan Gao
- & Alexander R. Ivanov
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Article
| Open AccessBacteroidota inhibit microglia clearance of amyloid-beta and promote plaque deposition in Alzheimer’s disease mouse models
The gut microbiota and microglia play critical roles in Alzheimer’s disease (AD). Here, the authors show that Bacteroides fragilis contributes to AD pathogenesis in mouse models by suppressing immune-mediated microglial clearance of amyloid beta.
- Caroline Wasén
- , Leah C. Beauchamp
- & Howard L. Weiner
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Review Article
| Open AccessCritical learning from industrial catalysis for nanocatalytic medicine
The knowledge gained from industrial catalysis benefits advancements of nanocatalytic medicines. Here the authors review the similarities, differences and connections in catalytic reactions between industrial and medical applications to support deep understanding and rational design of nanocatalytic medicines.
- Zhaokui Jin
- , Lingdong Jiang
- & Qianjun He
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Article
| Open AccessTLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: a randomized phase II Trial
Autologous tumor lysate (ATL) dendritic cell (DC) vaccination can induce local and systemic anti-tumor immune responses in malignant glioma patients. In this randomized phase II clinical trial, the authors evaluate the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to ATL-DC vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas.
- Richard G. Everson
- , Willy Hugo
- & Robert M. Prins
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Article
| Open AccessInterplay of structural preorganization and conformational sampling in UDP-glucuronic acid 4-epimerase catalysis
Enzymes involve structural flexibility in their function, but understanding enzyme catalysis as connected to protein motions is a major challenge. Here, the authors obtain energetic description of C-H activation in nicotinamide coenzyme-dependent UDP-glucuronic acid C4 epimerase based on temperature kinetic studies and isotope effect measurements.
- Christian Rapp
- , Annika Borg
- & Bernd Nidetzky
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Article
| Open AccessTemporal shifts in 24 notifiable infectious diseases in China before and during the COVID-19 pandemic
Public health and social measures for COVID-19 also impacted the incidence of other infectious diseases. In this study, the authors characterise the impacts of these measures on 24 notifiable infectious diseases in China until December 2023.
- Kangguo Li
- , Jia Rui
- & Tianmu Chen
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Article
| Open AccessThe differential impact of climate interventions along the political divide in 60 countries
A major barrier to climate mitigation is the political polarization of climate change. Here, the authors examine which of several interventions increase people’s climate policy support and climate action across ideological boundaries.
- Michael Berkebile-Weinberg
- , Danielle Goldwert
- & Madalina Vlasceanu
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Article
| Open AccessAllosteric regulation by c-di-AMP modulates a complete N-acetylglucosamine signaling cascade in Saccharopolyspora erythraea
c-di-AMP is essential for bacterial signaling. Here, the authors identify the GlcNAc-sensing regulator DasR as a c-di-AMP receptor and provide molecular insight into their signaling effect on the developmental and antibiotic biosynthesis control across Actinobacteria.
- Di You
- , Liu-Chang Zhao
- & Bang-Ce Ye
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Article
| Open AccessAn interphase actin wave promotes mitochondrial content mixing and organelle homeostasis
A mitochondrial actin wave fragments mitochondria. Here, the authors find that the wave produces force that is resisted by mitochondrial tethering, inducing fission, with subsequent fusion promoting mitochondrial content mixing and mitochondrial homeostasis.
- Stephen M. Coscia
- , Andrew S. Moore
- & Erika L. F. Holzbaur
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Article
| Open AccessPharmacological inhibition of α-synuclein aggregation within liquid condensates
Aggregated forms of α-synuclein are characteristic of Parkinson’s disease. Here the authors show that the condensation-driven aggregation pathway of α-synuclein can be inhibited using small molecules: the aminosterol claramine stabilizes α-synuclein condensates and inhibits α-synuclein primary nucleation in the aggregation process.
- Samuel T. Dada
- , Zenon Toprakcioglu
- & Michele Vendruscolo
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Article
| Open AccesstauFisher predicts circadian time from a single sample of bulk and single-cell pseudobulk transcriptomic data
There is a need to determine circadian time in gene expression datasets. Here, authors built tauFisher, a pipeline that predicts circadian time labels from single transcriptomic samples. tauFisher will be useful for determining body clock time in circadian medicine and for research.
- Junyan Duan
- , Michelle N. Ngo
- & Bogi Andersen
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Article
| Open AccessThe miR-144/Hmgn2 regulatory axis orchestrates chromatin organization during erythropoiesis
Differentiation of stem and progenitor cells is a highly regulated process. Here, the authors uncover miR-144 and its target Hmgn2 as the backbone of the genetic regulatory circuit that controls the terminal differentiation of erythrocytes in vertebrates.
- Dmitry A. Kretov
- , Leighton Folkes
- & Daniel Cifuentes
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Article
| Open AccessSpatially revealed roles for lncRNAs in Drosophila spermatogenesis, Y chromosome function and evolution
In Drosophila, long noncoding RNAs (lncRNAs) are expressed most highly in male germline cells. Here the authors report the subcellular distributions of approximately 600 Drosophila lncRNAs in male reproductive tissues, indicating potential involvement in spermatogenesis, fertility and evolution.
- Zhantao Shao
- , Jack Hu
- & Henry M. Krause
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Article
| Open AccessSeasonal antigenic prediction of influenza A H3N2 using machine learning
This study presents a machine learning model that accurately predicts seasonal antigenic changes of influenza A H3N2 using genetic data. The model’s predictions can aid influenza surveillance, vaccine strain selection, and public health management.
- Syed Awais W. Shah
- , Daniel P. Palomar
- & Matthew R. McKay
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Article
| Open AccessStructural basis for the intracellular regulation of ferritin degradation
Ferritin, the cellular iron storage complex, binds NCOA4 and is trafficked to the lysosome for degradation and iron release. Here, authors present the cryo-EM structure of the NCOA4-Ferritin complex with biophysical and cellular characterization.
- Fabian Hoelzgen
- , Thuy T. P. Nguyen
- & Gabriel A. Frank
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Article
| Open AccessSARS-CoV-2 Mpro responds to oxidation by forming disulfide and NOS/SONOS bonds
The main protease, a key enzyme of SARS-CoV-2, can protect itself from oxidative damage. Here, Reinke, Schubert, and colleagues used XFEL radiation to image the enzyme, revealing the disulfide and NOS/SONOS bonds that form in response to oxygen.
- Patrick Y. A. Reinke
- , Robin Schubert
- & Thomas J. Lane
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Article
| Open AccessHarnessing noncanonical crRNA for highly efficient genome editing
The inclusion of base Z has the potential to heighten the binding affinity between complementary nucleic acids. Here, the authors integrated base Z into CRISRP-Cas12a crRNA to augment the interaction between the crRNA and the target DNA, resulting in a significant enhancement of editing efficiency.
- Guanhua Xun
- , Zhixin Zhu
- & Huimin Zhao
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Article
| Open AccessA comprehensive genetic map of cytokine responses in Lyme borreliosis
Common genetic variants can affect an individual’s immune response to pathogens. Here, the authors uncover and characterize variants regulating cytokine responses in Lyme Borreliosis in 1,060 patients.
- Javier Botey-Bataller
- , Hedwig D. Vrijmoeth
- & Yang Li
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Article
| Open AccessImpact of distinct FG nucleoporin repeats on Nup98 self-association
Here, the authors demonstrate that mutations in the FG repeats of Nup98 significantly reduce its self-association capabilities and present a cryoEM structure exhibiting higher stability per residue then previously observed, suggesting spatial variations in self-association.
- Alain Ibáñez de Opakua
- , Christian F. Pantoja
- & Markus Zweckstetter
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Article
| Open AccessMetabolic phenotyping reveals an emerging role of ammonia abnormality in Alzheimer’s disease
Metabolic implications in AD are unclear. Here, authors found significant correlations between cognitive impairment and metabolic features in a Chinese aging cohort (n = 1397). The study highlights ammonia disturbance as a potential therapeutic target for AD.
- Tianlu Chen
- , Fengfeng Pan
- & Wei Jia
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Article
| Open AccessCRISPR-dCas13d-based deep screening of proximal and distal splicing-regulatory elements
Here the authors develop Splice-RUSH, a high-throughput screening method to map both proximal and distal splicing-regulatory sequences in a native sequence context. These sequences can also be targeted by ASOs to modulate splicing.
- Yocelyn Recinos
- , Dmytro Ustianenko
- & Chaolin Zhang
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Article
| Open AccessLower Ordovician synziphosurine reveals early euchelicerate diversity and evolution
Here, the authors describe an early synziphosurine from the Lower Ordovician Fezouata Shale of Morocco, which exhibits traits that elucidate the long-contentious relationships between crown euchelicerates and their sister taxa, and also clarifies euchelicerate body plan evolution.
- Lorenzo Lustri
- , Pierre Gueriau
- & Allison C. Daley
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Article
| Open AccessThe genomic landscape of Vk*MYC myeloma highlights shared pathways of transformation between mice and humans
Mouse models often combine mutant alleles to accelerate cancer development, limiting oncogenic diversity. Here the authors show that sporadic MYC activation in Vk*MYC mice is sufficient to induce tumors with a variety of secondary mutations that mirror the genetic heterogeneity of human myeloma.
- Francesco Maura
- , David G. Coffey
- & Marta Chesi
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Article
| Open AccessCardiac function is regulated by the sodium-dependent inhibition of the sodium-calcium exchanger NCX1
The sodium-calcium exchanger (NCX1) is the primary calcium extrusion mechanism of cardiac myocytes. Here, the authors show that removal of a long questioned allosteric regulation of NCX1 by intracellular sodium alters cardiac excitation-contraction coupling.
- Kyle Scranton
- , Scott John
- & Michela Ottolia
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Article
| Open AccessDeterminants of mosaic chromosomal alteration fitness
Here, the authors use passenger mutations to quantify expansion rate in ~6,000 people with mosaic chromosomal alterations in the NHLBI TOPMed cohort, finding associations between growth rate and blood counts along with germline genetic modulators of growth rate.
- Yash Pershad
- , Taralynn Mack
- & Alexander G. Bick
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Article
| Open AccessComplete male-to-female sex reversal in XY mice lacking the miR-17~92 cluster
The cluster miR-17~92 modulates the expression of genes networks and signalling pathways to ensure proper Sry expression timing and subsequent testis differentiation, an unexpected role for miRNAs in the early steps of mammalian sex determination.
- Alicia Hurtado
- , Irene Mota-Gómez
- & Francisco J. Barrionuevo
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Article
| Open AccessFGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma
FGFR inhibitors (FGFRi) benefit patients with FGFR2-fusion positive intrahepatic cholangiocarcinoma (ICC) but depth and duration of response is often limited. Here, the authors demonstrate that oncogenic FGFR2 signaling promotes a glycolytic phenotype, which is blocked by FGFRi, resulting in a targetable dependence on mitochondrial metabolism.
- Yuanli Zhen
- , Kai Liu
- & Nabeel Bardeesy
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Article
| Open AccessPersistent and multiclonal malaria parasite dynamics despite extended artemether-lumefantrine treatment in children
Standard diagnostics are often not able to fully capture submicroscopic parasite dynamics after treatment with antimalarials. In this longitudinal analysis of molecular markers of malaria parasitemia in an Ugandan cohort, authors describe persistence of markers following antimalarial therapy with dynamic and complex multiclonal infections in the initial and post-treatment periods.
- Justin Goodwin
- , Richard Kajubi
- & Sunil Parikh
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Article
| Open AccessSpecific exercise patterns generate an epigenetic molecular memory window that drives long-term memory formation and identifies ACVR1C as a bidirectional regulator of memory in mice
Exercise has beneficial effects on cognition. Here, authors utilize an exercise model to show ACVR1C to be an essential bidirectional regulator of memory and synaptic plasticity in adult, aging and 5xFAD mice beyond the context of exercise.
- Ashley A. Keiser
- , Tri N. Dong
- & Marcelo A. Wood
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Article
| Open AccessReplication competent HIV-guided CRISPR screen identifies antiviral factors including targets of the accessory protein Nef
Innate immune mechanisms are critical for antiviral defense. Here, the authors developed a CRISPR/Cas9-based HIV-driven approach to identify cellular factors compromising viral transcription, assembly, release or infectivity in human T cells. They identify targets of the Nef protein as antiviral factors.
- Caterina Prelli Bozzo
- , Alexandre Laliberté
- & Frank Kirchhoff
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Article
| Open AccessContextual and combinatorial structure in sperm whale vocalisations
Sperm whales use sequences of clicks to communicate. Here, the authors show that these vocalizations are significantly more complex than previously believed-the “sperm whale phonetic alphabet" has both combinatorial structure and call modulation dependent on the conversational context.
- Pratyusha Sharma
- , Shane Gero
- & Jacob Andreas
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Article
| Open AccessSleep fragmentation exacerbates myocardial ischemia‒reperfusion injury by promoting copper overload in cardiomyocytes
Sleep disorders increase the risk and mortality of heart disease. Here, the authors show that sleep fragmentation results in elevated copper levels in the male mouse heart and exacerbates myocardial ischemia–reperfusion injury with increased myocardial cuproptosis and apoptosis.
- Na Chen
- , Lizhe Guo
- & E. Wang
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Article
| Open AccessDistinct cellular immune responses in children en route to type 1 diabetes with different first-appearing autoantibodies
Previous studies have reported heterogeneity in the progression to clinical type 1 diabetes in children who develop either insulin- or glutamic acid decarboxylase-specific antibodies as their first autoantibodies. Here, the authors show that children who later develop disease have distinct characteristics in early immune responses, which are dependent on the type of autoantibodies that appear first.
- Inna Starskaia
- , Milla Valta
- & Riitta Lahesmaa
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Article
| Open AccessHigh SARS-CoV-2 incidence and asymptomatic fraction during Delta and Omicron BA.1 waves in The Gambia
Many low- and middle-income countries, including The Gambia, had low COVID-19 vaccination coverage during the emergence of the Delta and Omicron variants. Here, the authors perform a prospective household cohort study in the Gambia to investigate the dynamics of SARS-Cov-2 infection in this setting.
- Sheikh Jarju
- , Rhys D. Wenlock
- & Thushan I. de Silva
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