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| Open AccessCapturing heterogeneity in PDX models: representation matters
Patient derived tumor xenografts (PDXs) are important models for pre-clinical testing in cancer research and personalized medicine. PDXs often represent patient tumors with high similarity in terms of histology and driver mutations. However, certain limitations exist that warrant a detailed understanding of PDX heterogeneity and evolution. Hynds et al. demonstrate the relevance of primary tumor heterogeneity in PDX model establishment and explore multi-region sampling to determine the extent to which PDXs represent primary tumors.
- Hari Shankar Sunil
- & Kathryn A. O’Donnell
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Article
| Open AccessGlycolysis inhibition induces anti-tumor central memory CD8+T cell differentiation upon combination with microwave ablation therapy
Central memory CD8+ T cells (Tcm) are important for lasting anti-tumour immunity and their differentiation is determined by underpinning transcriptional and metabolic regulation. Authors here show that although microwave ablation (MWA) cancer therapy induces T cells to acquire some of the gene expression features of Tcms, but the full metabolic remodeling required for functionality is only achieved if glycolysis is inhibited simultaneously.
- Xinyu Tang
- , Xinrui Mao
- & Wenbin Zhou
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Article
| Open AccessRobotic versus laparoscopic distal gastrectomy for resectable gastric cancer: a randomized phase 2 trial
Robotic surgery has been demonstrated to improve short-term outcomes for patients with gastric cancer who received a gastrectomy, but the long-term effects are less clear. Here, the authors report the survival outcomes of their phase 2 randomized controlled trial comparing robotic to laparoscopic distal gastrectomy in patients with resectable gastric cancer.
- Jun Lu
- , Bin-bin Xu
- & Chang-Ming Huang
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Article
| Open AccessThe real-time infection hospitalisation and fatality risk across the COVID-19 pandemic in England
The severity of SARS-CoV-2 infection varied over the course of the pandemic due to factors such as changes in variant characteristics and population immunity from previous infection or vaccination. Here, the authors estimate infection hospitalisation and infection fatality rates in England over time from the start of the pandemic until March 2023.
- Thomas Ward
- , Martyn Fyles
- & Christopher E. Overton
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Article
| Open AccessThe thioredoxin system determines CHK1 inhibitor sensitivity via redox-mediated regulation of ribonucleotide reductase activity
The clinical application of inhibitors targeting checkpoint kinase 1 (CHK1) is challenged by limited efficacy. Here, the authors identify that thioredoxin (Trx) system inhibition mediates sensitivity to CHK1 inhibitor via regulating the activity of ribonucleotide reductase, demonstrating the synergistic effect of CHK1 inhibitor and inhibitors targeting Trx system in lung cancer models.
- Chandra Bhushan Prasad
- , Adrian Oo
- & Junran Zhang
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Article
| Open AccessThe chromatin landscape of pathogenic transcriptional cell states in rheumatoid arthritis
The epigenetic changes underlying the heterogeneity of RA disease presentation have been the subject of intense scrutiny. In this study, the authors use multiple single-cell sequencing datasets to define ‘chromatin superstates’ in patients with RA, which associate with distinct transcription factors and disease phenotypes.
- Kathryn Weinand
- , Saori Sakaue
- & Soumya Raychaudhuri
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Article
| Open AccessZDHHC20-mediated S-palmitoylation of YTHDF3 stabilizes MYC mRNA to promote pancreatic cancer progression
The relevance of post-translational modifications in pancreatic cancer remains insufficiently explored. Here, the authors report that ZDHHC20-mediated S-Palmitoylation of the m6A reader YTHDF3 stabilizes MYC mRNA to promote the progression of KRAS-mutant pancreatic cancer.
- Huan Zhang
- , Yan Sun
- & Xin Jin
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Article
| Open AccessAplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein
Pathologic α-synuclein spreads from cell-to-cell through binding to the lymphocyteactivation gene 3 (Lag3). Here, the authors demonstrate that the amyloid β precursor-like protein 1 (Aplp1) interacts with Lag3 and facilitates the binding, internalization, transmission, and toxicity of pathologic α-synuclein.
- Xiaobo Mao
- , Hao Gu
- & Ted M. Dawson
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Article
| Open AccessUniversal paramyxovirus vaccine design by stabilizing regions involved in structural transformation of the fusion protein
There is a lack of vaccines for prevention of human respirovirus 3 (RV3) infection. Bakkers et al. report the design of a stabilized RV3 preF protein vaccine candidate that induces strong neutralizing antibodies and protective responses in small animal models.
- Johannes P. M. Langedijk
- , Freek Cox
- & Mark J. G. Bakkers
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Article
| Open AccessPlasmodium falciparum infection in humans and mosquitoes influence natural Anopheline biting behavior and transmission
Mosquito biting preferences and their impact on malaria transmission are not well understood. Here, the authors report findings from a longitudinal cohort study in Western Kenya which show that males aged 5-15 years tend to be bitten the most, and infectious mosquitoes appear to be more likely to bite infected individuals.
- Christine F. Markwalter
- , Zena Lapp
- & Wendy Prudhomme O’Meara
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Review Article
| Open AccessRobotic wireless capsule endoscopy: recent advances and upcoming technologies
future requirements for intelligent wireless capsule endoscopy, providing a comparative evaluation of various methods’ merits and disadvantages, and highlighting recent developments in six technologies.
- Qing Cao
- , Runyi Deng
- & Dong Han
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Article
| Open AccessChronic intracranial recordings in the globus pallidus reveal circadian rhythms in Parkinson’s disease
The authors found that GPi circadian rhythms varied across individuals, with neural activity mainly decreasing at night but sometimes increasing. GPi circadian rhythms were frequency band-dependent and were modulated by the use of extended-release levodopa medication at night.
- Jackson N. Cagle
- , Tiberio de Araujo
- & Coralie de Hemptinne
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Article
| Open AccessDevelopment of a novel non-invasive biomarker panel for hepatic fibrosis in MASLD
Accurate non-invasive biomarkers to diagnose MASLD-related fibrosis are urgently needed. Here the authors show a disease mechanism-related blood-based biomarker panel consisting of three biomarkers which is able to accurately identify MASLD patients with mild or advanced hepatic fibrosis.
- Lars Verschuren
- , Anne Linde Mak
- & Roeland Hanemaaijer
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Article
| Open AccessGlucocorticoids paradoxically promote steroid resistance in B cell acute lymphoblastic leukemia through CXCR4/PLC signaling
Resistance to glucocorticoids (GC) is a major obstacle for the treatment of pediatric B-cell acute lymphoblastic leukemia (B-ALL). Here, the authors report that GC-triggered CXCR4 internalization promotes a phospholipase C (PLC)-mediated cell survival pathway, driving GC resistance in B-ALL.
- Souleymane Abdoul-Azize
- , Rihab Hami
- & Olivier Boyer
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Article
| Open AccessG protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits
Here authors aim to understand the 5-HT2AR coupling signature in response to different signaling probes and their physiological impacts using computational modeling, in vitro and in vivo experiments, and analysis of human brain tissue.
- Elk Kossatz
- , Rebeca Diez-Alarcia
- & Jana Selent
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Article
| Open AccessMucus production, host-microbiome interactions, hormone sensitivity, and innate immune responses modeled in human cervix chips
Human cervical mucosa and its interactions with the microbiome play a central role in female reproductive tract health and disease. Here, the authors develop physiological models of the human cervix using Organ-on-a-Chip technology that produce mucus, and respond to hormonal, environmental, and microbial cues similar to the living cervix.
- Zohreh Izadifar
- , Justin Cotton
- & Donald E. Ingber
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Article
| Open AccessA polygenic score method boosted by non-additive models
Polygenic scores aggregate the effects of multiple genetic variants and can be used to predict disease risk. Here, the authors present a polygenic score method that incorporates non-additive inheritance modes (recessive, dominant, over-recessive, and over-dominant) and show that this can improve risk prediction for certain polygenic diseases.
- Rikifumi Ohta
- , Yosuke Tanigawa
- & Shinichi Morishita
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Article
| Open AccessPancreatic beta-cell IL-22 receptor deficiency induces age-dependent dysregulation of insulin biosynthesis and systemic glucose homeostasis
IL-22RA1 is highly expressed on pancreatic islets and absent on immune cells. Here, the authors investigate its role by generating animals that lack IL-22RA1 on beta cells and reveal IL22RA1 signalling is critical for insulin biosynthesis and beta-cell health, evidenced by its regulation of MHC II expression and its suppressive effect on inflammation and cellular stress.
- Haressh Sajiir
- , Kuan Yau Wong
- & Sumaira Z. Hasnain
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Article
| Open AccessL-RNA aptamer-based CXCL12 inhibition combined with radiotherapy in newly-diagnosed glioblastoma: dose escalation of the phase I/II GLORIA trial
Recent studies show that targeting CXCL12 can improve the effect of radiotherapy (RT) in preclinical models of glioblastoma (GBM). Here, the authors report the safety and preliminary efficacy of a phase I/II clinical trial investigating an L-RNA aptamer-based CXCL12 inhibitor (NOX-A12) in combination with RT in patients with newly-diagnosed GBM.
- Frank A. Giordano
- , Julian P. Layer
- & Michael Hölzel
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Article
| Open AccessAssociations of semaglutide with incidence and recurrence of alcohol use disorder in real-world population
Anecdotal reports from patients prescribed semaglutide describe a reduced desire to drink. Here, the authors show that semaglutide is associated with a 50%-56% reduced risk for both the incidence and recurrence of alcohol use disorder in real-world populations.
- William Wang
- , Nora D. Volkow
- & Rong Xu
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Article
| Open AccessLong-read sequencing for 29 immune cell subsets reveals disease-linked isoforms
This paper unveils the complexity of human immune cell splicing, highlighting cell-specific isoforms and establishing connections between alternative splicing and complex traits. These findings have implications for understanding diseases and the evolution of the genome.
- Jun Inamo
- , Akari Suzuki
- & Yuta Kochi
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Article
| Open AccessStructure prediction of protein-ligand complexes from sequence information with Umol
Here the authors report the AI system Umol that predicts flexible all-atom structures of protein-ligand complexes from sequence information, advancing AI-driven drug discovery: accurate structures and affinity can be selected from predicted confidence metrics (plDDT).
- Patrick Bryant
- , Atharva Kelkar
- & Frank Noé
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Article
| Open AccessHuman movement and environmental barriers shape the emergence of dengue
Here, using a dynamic modelling approach, the authors find that the spread of dengue through Mexico and Brazil is shaped by specific interactions between human mobility, climate, and the environment. Their models can also be applied to predict future spread in these geographic areas.
- Vinyas Harish
- , Felipe J. Colón-González
- & Oliver J. Brady
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Article
| Open AccessGut microbiome remodeling and metabolomic profile improves in response to protein pacing with intermittent fasting versus continuous caloric restriction
Here, in a follow-up of a clinical study, the authors show that protein pacing and intermittent fasting improves gut symptomatology and microbial diversity, as well as reduces visceral fat compared to a heart-healthy, calorie-restricted diet matched for overall energy intake and expenditure in free-living humans.
- Alex E. Mohr
- , Karen L. Sweazea
- & Paul J. Arciero
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Article
| Open AccessProteomic analysis of the urothelial cancer landscape
Urothelial cancer is a challenging disease and an emerging field for targeted therapies. Here, the authors optimize clinical proteomics to provide proteome-level data on tumor specificity and identify robust prognostic subtypes with predictive information for repurposed drug candidates.
- Franz F. Dressler
- , Falk Diedrichs
- & Ákos Végvári
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Article
| Open AccessAcute and post-acute respiratory complications of SARS-CoV-2 infection: population-based cohort study in South Korea and Japan
Respiratory complications of SARS-CoV-2 infection have been described in the acute (within 30 days) and post-acute (after 30 days) phase. Here, the authors characterise the risk of acute and post-acute respiratory complications of SARS-CoV-2 using population-based data from South Korea and Japan.
- Yujin Choi
- , Hyeon Jin Kim
- & Dong Keon Yon
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Article
| Open AccessSafety outcomes following COVID-19 vaccination and infection in 5.1 million children in England
COVID-19 vaccines reduce the risk of severe disease in young people, but the absolute risk is low, and side effects have been reported. Here, the authors use data on 5–17 year olds in England to assess the overall risk-benefit profile of the vaccines.
- Emma Copland
- , Martina Patone
- & Julia Hippisley-Cox
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Article
| Open AccessNoninvasive imaging-guided ultrasonic neurostimulation with arbitrary 2D patterns and its application for high-quality vision restoration
Researchers have developed a noninvasive retina prosthesis based on ultrasound for treating blindness. This device uses ultrasound waves to stimulate the retina, creating artificial vision confirmed through behavior tests, offering a safer alternative to invasive treatments.
- Gengxi Lu
- , Chen Gong
- & Qifa Zhou
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Article
| Open AccessLongitudinal viral shedding and antibody response characteristics of men with acute infection of monkeypox virus: a prospective cohort study
Here the authors measure viral load in samples from skin lesions, saliva, oropharynx, and rectum of 77 patients with acute monkeypox virus infection as well as from environmental fomite swabs and show a high seropositivity rate for antibodies against A29L and H3L.
- Yang Yang
- , Shiyu Niu
- & Yingxia Liu
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Article
| Open AccessGlioblastoma disrupts cortical network activity at multiple spatial and temporal scales
The precise onset, temporal progression and spatial extent of neuron-tumor crosstalk in brain with Glioblastoma (GBM) are not fully understood. Here authors, using a genetic GBM mouse model, show widespread glutamate accumulation, chronic neural activity disruption between cells and brain areas, depending on tumor expansion rate and genotype with altered tumor and neural activity dynamics when adding glypican6.
- Jochen Meyer
- , Kwanha Yu
- & Jeffrey Noebels
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Article
| Open AccessC5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer
PARP inhibitors (PARPi) have been approved for the treatment of metastatic triple-negative breast cancer (BC), however resistance and recurrence are often observed. Here, in preclinical models of BRCA1/2 wild type and homologous recombination competent BC, the authors show that C5aR1-positive tumor associated macrophages are associated with PARPi-resistance, suggesting targeting C5aR1 as a therapeutic option.
- Xi Li
- , Alfonso Poire
- & Gordon B. Mills
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Article
| Open AccessLateral parabrachial FoxP2 neurons regulate respiratory responses to hypercapnia
The parabrachial nucleus contains separate populations of neurons that respond to elevated CO2 with EEG arousal and increased breathing. Here we report that the parabrachial respiratory neurons express FoxP2 and are required for respiratory responses to elevated CO2.
- Satvinder Kaur
- , Nicole Lynch
- & Clifford B. Saper
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Article
| Open AccessImmune features are associated with response to neoadjuvant chemo-immunotherapy for muscle-invasive bladder cancer
In the phase 2 study LCCC1520 (NCT02690558), clinical activity of pembrolizumab in combination with gemcitabine and cisplatin as neoadjuvant therapy in patients with muscle-invasive bladder cancer has been reported. Here the authors present molecular and immune cellular features associated with response to neoadjuvant chemo-immunotherapy.
- Wolfgang Beckabir
- , Mi Zhou
- & Benjamin G. Vincent
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Article
| Open AccessHIV-1 RNA in extracellular vesicles is associated with neurocognitive outcomes
Despite effective antiviral drugs, HIV-1 transcripts can be found in extracellular vesicles (EVs) in people living with HIV-1. Comparing EVs from serum and cerebrospinal fluid (CSF), the authors show compartmentalized defective viral transcripts that are enriched in the CSF and corelate with cognitive dysfunction.
- Catherine DeMarino
- , Julia Denniss
- & Avindra Nath
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Article
| Open AccessThe brain structure, inflammatory, and genetic mechanisms mediate the association between physical frailty and depression
Identifying modifiable risk factors that could prevent depression is important. Here, the authors show increased risks of incident depression in pre-frail and frail individuals and highlight the mediating role of brain structure and inflammation.
- Rongtao Jiang
- , Stephanie Noble
- & Dustin Scheinost
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Article
| Open AccessReduction of specific enterocytes from loss of intestinal LGR4 improves lipid metabolism in mice
How LGR4 impacts nutrition absorption and energy homeostasis is unknown. Here, the authors show that LGR4 loss in the intestinal epithelium decreases the proportion of enterocytes selective for long-chain fatty acid absorption, reducing lipid absorption and improving lipid and glucose metabolism.
- Yuan Liang
- , Chao Luo
- & Yue Yin
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Article
| Open AccessSingle-cell and spatial transcriptomics analysis of non-small cell lung cancer
Myeloid cell populations play a critical role in lung cancer progression. Here, the authors use scRNA-seq and spatial transcriptomics to identify changes in the phenotype of macrophages within the tumour microenvironment.
- Marco De Zuani
- , Haoliang Xue
- & Ana Cvejic
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Article
| Open AccessA nutrient responsive lipase mediates gut-brain communication to regulate insulin secretion in Drosophila
Amplification of glucose stimulated insulin secretion by lipids is not fully understood due to complex inter organ communication in glycemic regulation. Here the authors show Vaha, a Drosophila lipase synthesized in the gut, concentrates in insulin producing cells in the brain to regulate insulin like peptide release.
- Alka Singh
- , Kandahalli Venkataranganayaka Abhilasha
- & Usha R. Acharya
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Article
| Open AccessCompound mortality impacts from extreme temperatures and the COVID-19 pandemic
Extreme weather and pandemics are classified as two of the most serious risks facing the UK in its National Risk Register. Here, the authors investigate the compound mortality impacts of extreme high and low temperatures and COVID-19 in England and Wales.
- Y. T. Eunice Lo
- , Dann M. Mitchell
- & Antonio Gasparrini
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Article
| Open AccessPost-COVID conditions following COVID-19 vaccination: a retrospective matched cohort study of patients with SARS-CoV-2 infection
The impact of COVID-19 vaccination on post-COVID conditions is not well understood. Here, the authors use electronic health record data from a network of eight integrated healthcare systems in the United States to compare rates of post-COVID conditions in those with and without vaccination.
- Debbie E. Malden
- , In-Lu Amy Liu
- & Sara Y. Tartof
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Article
| Open AccessUnveiling unique clinical phenotypes of hip fracture patients and the temporal association with cardiovascular events
Cardiovascular events (CVEs) are the leading cause of death among hip fracture patients. Here, the authors show the findings on subphenotyping the heterogeneous spectrum of hip fracture patients in both Hong Kong and the United Kingdom older adult populations and temporal associations with CVEs across all subphenotypes.
- Warrington W. Q. Hsu
- , Xiaowen Zhang
- & Ching-Lung Cheung
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Article
| Open AccessIntegrating human endogenous retroviruses into transcriptome-wide association studies highlights novel risk factors for major psychiatric conditions
Duarte et al. report that common genetic variants linked to psychiatric disorders influence the regulation of ancient retroviruses integrated into the genome. This suggests ancient viruses acquired millions of years ago may have shaped modern human brain function.
- Rodrigo R. R. Duarte
- , Oliver Pain
- & Timothy R. Powell
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Article
| Open AccessArtificial intelligence enables precision diagnosis of cervical cytology grades and cervical cancer
Cervical screening is a key method for detecting cervical cancer, but is limited by pathologist detection. Here, the authors use artificial intelligence to predict cytology grades from whole slide images.
- Jue Wang
- , Yunfang Yu
- & Herui Yao
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Article
| Open AccessDrug screening on digital microfluidics for cancer precision medicine
In-vitro platforms for personalized cancer diagnosis is required high sensitivity. Here, the authors developed a digital microfluidic system for drug screening using primary tumor cells and established a working protocol for precision medicine.
- Jiao Zhai
- , Yingying Liu
- & Yanwei Jia
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Article
| Open AccessHippocampal sharp-wave ripples correlate with periods of naturally occurring self-generated thoughts in humans
Whether and how sharp-wave ripples (SWRs) accompany mental states that are less closely linked to events in the immediate environment are not fully understood. Here authors recorded SWRs from hippocampus of 10 epilepsy patients for up to 15 days with experience sampling. SWR rates showed circadian fluctuation and were associated with self-generated thoughts such as mind wandering.
- Takamitsu Iwata
- , Takufumi Yanagisawa
- & Haruhiko Kishima
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Article
| Open AccessCiliary tip actin dynamics regulate photoreceptor outer segment integrity
Photoreceptor outer segment abnormalities cause retinitis pigmentosa, a form of blindness. Here, authors show that the disease-associated gene RPGR regulates actin-mediated outer segment turnover through its interaction with the actin severer, cofilin.
- Roly Megaw
- , Abigail Moye
- & Pleasantine Mill
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Article
| Open AccessDisruption of TIGAR-TAK1 alleviates immunopathology in a murine model of sepsis
Macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) is implicated in a range of immunopathology. Here the authors show TIGAR drives inflammation and sepsis via activation of TAK1 and that disruption of TIGAR-TAK1 interaction in a murine model of sepsis reduces immunopathology.
- Dongdong Wang
- , Yanxia Li
- & Jingjing Ben
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Article
| Open AccessIn vivo neutralization of coral snake venoms with an oligoclonal nanobody mixture in a murine challenge model
Oligoclonal mixtures of neutralising antibodies can target multiple antigen components and represent a potential therapeutic solution for the treatment of envenomation. Here, the authors generate mixtures of nanobodies against coral snake venom toxins and demonstrate they can prevent lethality of coral snake venoms in pre-clinical animal models.
- Melisa Benard-Valle
- , Yessica Wouters
- & Andreas Hougaard Laustsen
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Article
| Open AccessFluorescent fatty acid conjugates for live cell imaging of peroxisomes
The array of tools to image peroxisome regulation is still limited. Here, the authors develop improved fatty acid-based probes with high peroxisome specificity and bright fluorescence in the red/far-red spectrum, which makes them ideal to study peroxisomes in live cells and whole organisms.
- Daria Korotkova
- , Anya Borisyuk
- & Triana Amen