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| Open AccessQuantifying 3′UTR length from scRNA-seq data reveals changes independent of gene expression
While gene expression analysis is commonly performed, 3′UTR length analysis is limited due to technical challenges. Here the authors provide an open-access analysis pipeline for scRNA-seq data to simultaneously quantify gene expression and 3′UTR length.
- Mervin M. Fansler
- , Sibylle Mitschka
- & Christine Mayr
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Article
| Open AccessGRouNdGAN: GRN-guided simulation of single-cell RNA-seq data using causal generative adversarial networks
Benchmarking GRN inference methods remains a challenge. Here, authors present GRouNdGAN, a causal generative model that imposes a user-defined GRN in its architecture to simulate realistic single-cell data, bridging the gap between synthetic and biological data benchmarks of GRN inference methods.
- Yazdan Zinati
- , Abdulrahman Takiddeen
- & Amin Emad
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Article
| Open AccessEnzyme-assisted high throughput sequencing of an expanded genetic alphabet at single base resolution
The expansion of the genetic code with synthetic nucleotides has broadened our ability to evolve DNA as a functional material, but we lack analytical tools for the expanded alphabet. Here the authors demonstrate an enzyme-assisted method for the sequencing of six-letter DNA.
- Bang Wang
- , Kevin M. Bradley
- & Steven A. Benner
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Article
| Open AccessDouble-negative B cells and DNASE1L3 colocalise with microbiota in gut-associated lymphoid tissue
Intestinal homeostasis is maintained by interactions between the gut-associated lymphoid tissue and the resident flora. Here Montorsi et al use multiplexed single cell omics to describe double negative type 2 B cells and DNASE1L3-expressing dendritic cells that interact and associate with microbiota on the human gut antigenic front line.
- Lucia Montorsi
- , Michael J. Pitcher
- & Jo Spencer
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Article
| Open AccessTransfer learning enables identification of multiple types of RNA modifications using nanopore direct RNA sequencing
Simultaneous profiling of multiple RNA modifications is a promising yet understudied field of research. Here, authors develop a transferable deep learning framework capable of detecting multiple types of RNA modifications in single nanopore sequencing sample.
- You Wu
- , Wenna Shao
- & Xiang Yu
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Article
| Open AccessSystematic dissection of tumor-normal single-cell ecosystems across a thousand tumors of 30 cancer types
Single-cell sequencing has enabled detailed analyses of the tumour microenvironment (TME). Here, the authors perform an integrative analysis of the TME using single-cell and spatial transcriptomics data from over a thousand tumours across thirty cancer types, identifying interferon-enriched community states predictive of immunotherapeutic responses.
- Junho Kang
- , Jun Hyeong Lee
- & Jong-Eun Park
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Article
| Open AccessTranscription stress at telomeres leads to cytosolic DNA release and paracrine senescence
Cellular senescence and the process of transcription are intimately linked, yet the mechanisms involved remain unclear. Here the authors show that a defect in TFIIS leads to telomere dysfunction, genome instability and the release of vesicles that induce senescence to neighboring cells.
- Athanasios Siametis
- , Kalliopi Stratigi
- & George A. Garinis
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Article
| Open AccessDrosophila Evi5 is a critical regulator of intracellular iron transport via transferrin and ferritin interactions
Vesicle transport ensures cargo delivery to cellular targets. Here, Soltani et al. show that Drosophila Evi5, a multiple sclerosis risk gene in humans, controls vesicular transport of iron-bound transferrins and physically interacts with ferritin.
- Sattar Soltani
- , Samuel M. Webb
- & Kirst King-Jones
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Article
| Open AccessDynamin1 long- and short-tail isoforms exploit distinct recruitment and spatial patterns to form endocytic nanoclusters
Dynamins are required at nascent endosomes to promote membrane fission. Here, the authors use super-resolution microscopy to show that dynamin-1 recruitment relies on pre-existing nanoclusters and trapping of molecules laterally diffusing on the plasma membrane.
- Anmin Jiang
- , Kye Kudo
- & Frédéric A. Meunier
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Article
| Open AccessChemical manipulation of an activation/inhibition switch in the nuclear receptor PXR
PXR is a receptor activated by diverse compounds that triggers detoxification pathways in the cell, and blocking this receptor may increase the effectiveness of certain drugs. Here, the authors present the structural basis of PXR inhibition.
- Efren Garcia-Maldonado
- , Andrew D. Huber
- & Taosheng Chen
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Article
| Open AccessLong-read powered viral metagenomics in the oligotrophic Sargasso Sea
The Sargasso Sea is a natural laboratory for understanding future conditions of warmer oceans and associated nutrient limitation. Here, the authors combined short- and long-read sequencing to survey Sargasso Sea viral communities.
- Joanna Warwick-Dugdale
- , Funing Tian
- & Ben Temperton
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Article
| Open AccessProteome partitioning constraints in long-term laboratory evolution
Adaptive laboratory evolution provides a real-time record of physiological change. In bacteria adapted to glucose over 40 000 generations, this study finds an apparent increase in enzyme efficiency consistent with increased substrate saturation due to loss of a flux sensing mechanism early in adaptation.
- Matteo Mori
- , Vadim Patsalo
- & Matthew Scott
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Article
| Open AccessChildren exhibit superior memory for attended but outdated information compared to adults
Children typically exhibit weaker memory than adults. Here, the authors report a developmental reversal-like phenomenon that children show better memory for attended but outdated information, suggesting underdeveloped memory selection in children.
- Yingtao Fu
- , Tingyu Guo
- & Hui Chen
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Article
| Open AccessmTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism
How cells adapt to glucose starvation is still elusive. Here, Levy et al. show that the mTOR substrate 4EBP1 protects human, mouse, and yeast cells from glucose starvation and is exploited by cancer cells to promote tumorigenesis.
- Tal Levy
- , Kai Voeltzke
- & Gabriel Leprivier
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Article
| Open AccessTargeted protein degradation in mycobacteria uncovers antibacterial effects and potentiates antibiotic efficacy
Efforts to apply targeted protein degradation for antibiotic development are limited by our understanding of prokaryotic protein degradation. Here, the authors establish a chemical-genetic platform and predictive model to determine the degradation potential of essential mycobacterial proteins.
- Harim I. Won
- , Samuel Zinga
- & Junhao Zhu
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Article
| Open AccessDysfunctional adipocytes promote tumor progression through YAP/TAZ-dependent cancer-associated adipocyte transformation
The impact of obesity on cancer remains insufficiently explored. Here the authors show that in mouse models, dysfunctional adipocytes exhibit low levels of BECN1 which induce YAP/TAZ activity to promote breast and colorectal tumor progression.
- Yaechan Song
- , Heeju Na
- & Han-Woong Lee
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Article
| Open AccessSafety, immunogenicity and efficacy of the self-amplifying mRNA ARCT-154 COVID-19 vaccine: pooled phase 1, 2, 3a and 3b randomized, controlled trials
In this randomized, controlled integrated phase 1/2/3a/3b clinical trial, the authors show that the self-amplifying mRNA COVID-19 vaccine ARCT-154 shows good immunogenicity and is safe and efficient against COVID-19 (57% against any COVID-19, and 95% against severe COVID-19).
- Nhân Thị Hồ
- , Steven G. Hughes
- & Xuan-Hung Nguyen
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Article
| Open AccessAlpha-glucans from bacterial necromass indicate an intra-population loop within the marine carbon cycle
Phytoplankton blooms provoke bacterioplankton blooms, from which bacterial biomass (necromass) is released via zooplankton grazing and viral lysis. Here, Beidler et al. show that the bacterial biomass, including alpha-glucan polysaccharides generated from the consumption of algal organic matter, is reused by microbes in vitro and during a diatom-dominated bloom.
- Irena Beidler
- , Nicola Steinke
- & Thomas Schweder
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Article
| Open AccessThree-dimensional liquid metal-based neuro-interfaces for human hippocampal organoids
Providing a suitable multi-electrode array (MEA) for free-floating neural organoids is a great challenge. Here, authors present a mesh soft stretchable MEA for recording neural signals in human hippocampal organoids derived from induced pluripotent stem cells.
- Yan Wu
- , Jinhao Cheng
- & Xingyu Jiang
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Article
| Open AccessPremature skewing of T cell receptor clonality and delayed memory expansion in HIV-exposed infants
Here, Dzanibe et al show that in utero HIV/ARV exposure sequentially disrupts infant immunologic trajectories, beginning with NK cells that predict vaccine antibody responses and followed by delayed T cell memory maturation linked to skewed TCR clonality.
- Sonwabile Dzanibe
- , Aaron J. Wilk
- & Clive M. Gray
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Article
| Open AccessAnalysis of nearly 3000 archaeal genomes from terrestrial geothermal springs sheds light on interconnected biogeochemical processes
Here, Qi et al. assembled ~3000 archaeal genomes from hot springs, capturing temporal dynamics and environmental diversity, and systematically explored functional niches and metabolic handoffs, shedding light on Archaea’s role in biogeochemical cycling.
- Yan-Ling Qi
- , Ya-Ting Chen
- & Zheng-Shuang Hua
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Article
| Open AccessFunctional and antigenic characterization of SARS-CoV-2 spike fusion peptide by deep mutational scanning
Deep mutational scanning experiments on an S2 region spanning the fusion peptide of authentic SARS-CoV-2 with different cell lines revealed that mutations at residue 813 of the spike protein reduced TMPRSS2-mediated entry with decreased virulence.
- Ruipeng Lei
- , Enya Qing
- & Lok-Yin Roy Wong
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Article
| Open AccessDe novo motor learning creates structure in neural activity that shapes adaptation
Using recurrent neural networks, here the authors show that learning the same task through different experiences can lead to important differences in how neural activity is structured. These differences can play a crucial role for subsequent adaptation, with networks that are equally good at the initial task showing opposing trends in adaptation.
- Joanna C. Chang
- , Matthew G. Perich
- & Claudia Clopath
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Article
| Open AccessdsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe
Anaplastic thyroid cancer (ATC) is a particularly aggressive cancer type with limited effective therapeutic options. Here, the authors identify the SUMO E3 ligase PIAS2 as a potential therapeutic target in ATC and mechanistically investigate its role in mitotic spindle and centrosome assembly.
- Joana S. Rodrigues
- , Miguel Chenlo
- & Clara V. Alvarez
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Article
| Open AccessPrimacy of vision shapes behavioral strategies and neural substrates of spatial navigation in marmoset hippocampus
How diurnal primates develop exploration-navigation strategy and how the physiology of primate hippocampus is shaped in navigation are not fully understood. Here authors show that marmosets adapted their navigation strategies to their diurnal ecological niche. Notably, marmoset hippocampal neurons are specialized for encoding combinations of view, head direction and place, and that theta oscillations are triggered by rapid head-gaze movements.
- Diego B. Piza
- , Benjamin W. Corrigan
- & Julio Martinez-Trujillo
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Article
| Open AccessSevere outcomes of malaria in children under time-varying exposure
Severe pediatric malaria remains a concern in many countries. Here, the authors use an individual-based modeling approach to evaluate the relationship between malaria prevalence and incidence of malaria pediatric hospitalizations, and show how unsteady transmission patterns affect hospitalization rates.
- Pablo M. De Salazar
- , Alice Kamau
- & Melissa A. Penny
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Article
| Open AccessLoCoHD: a metric for comparing local environments of proteins
The techniques available for comparing protein structures do not focus directly on the chemical nature of residue environments. Here, authors describe a computational method that can capture both the spatial and chemical dissimilarities of residue surroundings.
- Zsolt Fazekas
- , Dóra K. Menyhárd
- & András Perczel
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Article
| Open AccessDeep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants
The details of how the protein folding and degradation systems collaborate to combat potentially toxic non-native proteins are unknown. Here the authors perform systematic studies of missense and nonsense variants of the cytosolic aspartoacylase, ASPA, where loss-of-function variants are linked to Canavan disease.
- Martin Grønbæk-Thygesen
- , Vasileios Voutsinos
- & Rasmus Hartmann-Petersen
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Article
| Open AccessOxidative photocatalysis on membranes triggers non-canonical pyroptosis
Oxidative damage to intracellular membrane proteins is critical to cells. Here, the authors use a water-oxidizing photocatalyst, generating ∙OH even under hypoxia, to show that membrane-specific protein oxidation triggers pyroptosis via non-canonical inflammasomes.
- Chaiheon Lee
- , Mingyu Park
- & Tae-Hyuk Kwon
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Article
| Open AccessMicrofibril-associated glycoprotein 4 forms octamers that mediate interactions with elastogenic proteins and cells
Microfibrillar-associated protein 4 (MFAP4) is involved in fibrotic and cardiovascular diseases. Wozny et al. reveal structural aspects mediating MFAP4 octamer formation critical for its interaction with elastogenic proteins and cells.
- Michael R. Wozny
- , Valentin Nelea
- & Dieter P. Reinhardt
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Article
| Open AccessStructural and dynamic insights into the activation of the μ-opioid receptor by an allosteric modulator
Here, the authors utilise NMR and cryo-EM to characterise the binding of an allosteric modulator to μ-opioid receptor (MOR), revealing modulator binding can potentiate receptor activation by altering the conformational dynamics in the core region of MOR.
- Shun Kaneko
- , Shunsuke Imai
- & Ichio Shimada
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Article
| Open AccessMethylation of ESCRT-III components regulates the timing of cytokinetic abscission
Methylation of CHMP2B regulates abscission timing by modulating ESCRT-III dynamics during cytokinesis. This methylation also plays a role in HIV-1 budding, highlighting the broader significance of ESCRT-III methylation.
- Aurélie Richard
- , Jérémy Berthelet
- & Souhila Medjkane
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Article
| Open AccessMultiscale modelling of chromatin 4D organization in SARS-CoV-2 infected cells
In this work, the authors apply polymer models to reconstruct the 3D structure of the genome during SARS-CoV-2 infection and examine how the virus impacts key mechanisms of chromatin organization.
- Andrea M. Chiariello
- , Alex Abraham
- & Mario Nicodemi
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Article
| Open AccessAnalysis of early intermediate states of the nitrogenase reaction by regularization of EPR spectra
Here, the authors characterize selenium and sulphur incorporated FeMo cofactors of the catalytic MoFe protein component from Azotobacter vinelandii under turnover conditions using EPR.
- Lorenz Heidinger
- , Kathryn Perez
- & Erik Schleicher
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Article
| Open AccessCoordinated wound responses in a regenerative animal-algal holobiont
The term ‘holobiont’ refers to a multicellular organism and its microbial symbionts. Whether and how symbionts react to host injury and how cellular responses are integrated across species remain unexplored. Here, the authors report a deeply conserved animal regeneration regulatory program that links molecular networks across species in an animal-algal holobiont.
- Dania Nanes Sarfati
- , Yuan Xue
- & Bo Wang
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Article
| Open AccessMapping of mitogen and metabolic sensitivity in organoids defines requirements for human hepatocyte growth
Human hepatocytes remain hard to grow in vitro. Here, the authors temporally map the early stages of organoid growth initiated from fetal and adult hepatocytes, leveraging this knowledge to design maturation and improved expansion conditions.
- Delilah Hendriks
- , Benedetta Artegiani
- & Hans Clevers
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Article
| Open AccessNonuniform and pathway-specific laminar processing of spatial frequencies in the primary visual cortex of primates
The uniformity of laminar processing in a cortex remains not fully understood. Here authors show that high spatial frequency stimuli elicit distinct active patterns across V1 layers, arising from multiple mechanisms involving M and P pathways.
- Tian Wang
- , Weifeng Dai
- & Dajun Xing
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Article
| Open AccessThe structural basis for 2′−5′/3′−5′-cGAMP synthesis by cGAS
Here, the authors provide structural and biochemical data describing the mechanism through which cGAS synthesizes 2′−5′/3′−5′-cGAMP.
- Shuai Wu
- , Sandra B. Gabelli
- & Jungsan Sohn
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Article
| Open AccessGene editing for latent herpes simplex virus infection reduces viral load and shedding in vivo
The main challenge for anti-HSV therapy is to target latent virus in ganglionic neurons. Here, the authors report a well-tolerated anti-HSV gene editing approach against HSV which targets latent HSV genomes and leads to reductions of ganglionic viral loads, and viral shedding upon reactivation in mouse models.
- Martine Aubert
- , Anoria K. Haick
- & Keith R. Jerome
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Article
| Open AccessThe basal forebrain to lateral habenula circuitry mediates social behavioral maladaptation
Maladaptive fear is linked to many neuropsychiatric disorders, while its neural basis is not fully understood. Here, the authors show that the hyperactivity of the basal forebrain to lateral habenula glutamatergic circuit is crucial for social fear behavior.
- Jun Wang
- , Qian Yang
- & Han Xu
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Article
| Open AccessTargeting bacterial nickel transport with aspergillomarasmine A suppresses virulence-associated Ni-dependent enzymes
Aspergillomarasmine A (AMA) chelates metal ions such as Zn2+ and Ni2+, which are essential for the activity of enzymes that are important for virulence of several pathogens. Here, Sychantha et al. show that AMA inhibits bacterial Ni2+ uptake and Ni-dependent enzymes, and reduces bacterial virulence in an animal infection model.
- David Sychantha
- , Xuefei Chen
- & Gerard D. Wright
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Article
| Open AccessMammographic density mediates the protective effect of early-life body size on breast cancer risk
Mammographic density is known to be linked to breast cancer risk. Here, the authors use Mendelian randomization to estimate the effects of childhood body size and age at menarche on density phenotypes and breast cancer risk.
- Marina Vabistsevits
- , George Davey Smith
- & Eleanor Sanderson
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Article
| Open AccessDynamic microvilli sculpt bristles at nanometric scale
Bristleworms possess dedicated cells that can synthesize highly stereotypical bristles with sub-micrometric precision. Here, Ikeda and colleagues shed light on the underlying dynamics of cellular protrusions, revealing an extension-disassembly cycle that resembles a 3D printer.
- Kyojiro N. Ikeda
- , Ilya Belevich
- & Florian Raible
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Article
| Open AccessPlatelets favor the outgrowth of established metastases
It is unclear if platelets regulate the growth of established metastases. Using syngeneic mouse models of metastasis, the authors show that platelets support the outgrowth of established metastases via immune suppression, and that targeting the platelet-specific receptor GPVI, efficiently reduces established metastases, providing a promising therapeutic avenue for inhibiting cancer metastasis.
- Maria J. Garcia-Leon
- , Cristina Liboni
- & Jacky G. Goetz
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Article
| Open AccessA cell-free nutrient-supplemented perfusate allows four-day ex vivo metabolic preservation of human kidneys
As demand for organ transplants exceeds availability there has been an unmet need to extend preservation of deceased donor kidneys. Here, the authors show that a cell-free nutrient-supplemented perfusate allows 4-day preservation of human kidneys using spatially resolved lipidomics and metabolomics.
- Marlon J. A. de Haan
- , Marleen E. Jacobs
- & Ton J. Rabelink
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Article
| Open AccessRelationship between HLA genetic variations, COVID-19 vaccine antibody response, and risk of breakthrough outcomes
Human leucocyte antigens are important in the adaptive immune response. Here, the authors use data from the UK Biobank linked to electronic health records to investigate the association between genetic variation in HLA alleles and antibody responses to SARS-CoV-2 vaccination and breakthrough COVID-19 outcomes.
- Junqing Xie
- , Beatriz Mothe
- & Daniel Prieto Alhambra
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Article
| Open AccessStructural basis of human NOX5 activation
NADPH oxidase 5 (NOX5) is activated by Ca2+ signaling, catalyzing superoxide production by transferring electrons from intracellular NADPH to extracellular oxygen. Here the authors uncover the molecular basis of NOX5 activation and electron transfer.
- Chenxi Cui
- , Meiqin Jiang
- & Ji Sun
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Article
| Open AccessEnhancing genome editing in hPSCs through dual inhibition of DNA damage response and repair pathways
Precise genome editing is crucial. Here the authors demonstrate that dual inhibition of p53-mediated cell death and distinct activation of the DNA damage repair system upon DNA damage by cytosine base editor (CBE) or prime editor (PE) additively enhanced editing efficiency in hPSCs.
- Ju-Chan Park
- , Yun-Jeong Kim
- & Hyuk-Jin Cha
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Article
| Open AccessStructural insights into drug transport by an aquaglyceroporin
Pentamidine and melarsoprol are drugs used to treat sleeping sickness caused by Trypanosoma brucei. Here, authors present cryo-EM structures of TbAQP2 with molecular dynamic simulations, revealing mechanisms shaping substrate specificity and drug permeation.
- Wanbiao Chen
- , Rongfeng Zou
- & Chongyuan Wang
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