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| Open AccessDopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo
Here, the authors report that schizophrenia risk variants mapping to a striatal dopamine-related gene set are associated with increased striatal dopamine synthesis capacity and increased striatal activity during reward anticipation in humans.
- Leonardo Sportelli
- , Daniel P. Eisenberg
- & Giulio Pergola
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| Open AccessProtein mimetic 2D FAST rescues alpha synuclein aggregation mediated early and post disease Parkinson’s phenotypes
The aggregation of the neuronal protein α-Synuclein is associated with the onset of Parkinson’s disease. Here the authors report a two-dimensional Fragment Assisted Structure-based technique to find antagonists of α-Synuclein aggregation and show its promise for identifying lead therapeutics for Parkinson’s disease.
- Nicholas H. Stillman
- , Johnson A. Joseph
- & Sunil Kumar
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| Open AccessDynamic diversity of SARS-CoV-2 genetic mutations in a lung transplantation patient with persistent COVID-19
In this study, the authors report the case of a patient who underwent lung transplantation and subsequently developed COVID-19 that resulted in persistent infection. Following antiviral treatment, SARS-CoV-2 (BA.5) showed dynamic genetic diversity with remdesivir resistant mutations leading to enhanced fusogenicity.
- Hidetoshi Igari
- , Seiichiro Sakao
- & Eiji Ido
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| Open AccessA secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1
Triazole antifungals are widely used and exert their action by inhibiting ergosterol biosynthesis. Here, Rybak et al show that these drugs both inhibit ergosterol biosynthesis and induce accumulation of pathway intermediates that directly induce inhibition of sterol synthesis.
- Jeffrey M. Rybak
- , Jinhong Xie
- & Jarrod R. Fortwendel
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Article
| Open AccessGut microbiome composition and metabolic activity in women with diverticulitis
Here, the authors present a multi-omics examination of stool samples obtained from individuals with diverticulitis and controls, uncovering disruptions in the balance of microbial composition and metabolites, as well as co-occurring microbe-metabolite associations relevant to the disease.
- Wenjie Ma
- , Yiqing Wang
- & Andrew T. Chan
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| Open AccessIdentifying therapeutic targets for cancer among 2074 circulating proteins and risk of nine cancers
Circulating proteins are a potential source of cancer biomarkers. Here, the authors assessed 2,074 circulating proteins and used Mendelian randomisation to compare with the risk of 9 common cancer types across multiple GWAS cohorts and identified key considerations with respect to the potential for adverse effects of altering cancer-risk proteins that inform their utility in cancer prevention.
- Karl Smith-Byrne
- , Åsa Hedman
- & Anders Mälarstig
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| Open AccessMitochondrial complex I deficiency stratifies idiopathic Parkinson’s disease
Idiopathic Parkinson’s disease can be stratified according to the severity of neuronal respiratory complex I deficiency. The emerging disease subtypes show distinct molecular and clinical profiles.
- Irene H. Flønes
- , Lilah Toker
- & Charalampos Tzoulis
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| Open AccessIndividualized prevention of proton pump inhibitor related adverse events by risk stratification
The safety profile of proton pump inhibitor (PPI) use remains controversial. Here, the authors show that PPI use is associated with an increased risk of 15 leading global diseases, with absolute risks increasing with baseline risks, highlighting the need for personalized PPI use strategies.
- Bin Xia
- , Qiangsheng He
- & Jinqiu Yuan
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Article
| Open AccessReservoir displacement by an invasive rodent reduces Lassa virus zoonotic spillover risk
Mastomys natalensis is a rodent species native to West Africa that is the primary reservoir host for Lassa virus. Here, the authors investigate whether the invasive rodent Rattus rattus decreases M. natalensis density and could therefore indirectly decrease zoonotic transmission of Lassa virus to humans.
- Evan A. Eskew
- , Brian H. Bird
- & Scott L. Nuismer
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Article
| Open AccessMacrophage-fibroblast JAK/STAT dependent crosstalk promotes liver metastatic outgrowth in pancreatic cancer
An inflammatory-fibrotic tumor microenvironment supports metastatic disease progression in pancreatic ductal adenocarcinoma (PDAC). Here the authors show that metastasis-infiltrating macrophages influence metastasis-associated fibroblast (MAF) heterogeneity in liver metastatic PDAC, by promoting JAK/STAT signalling pathway activation in MAFs.
- Meirion Raymant
- , Yuliana Astuti
- & Michael C. Schmid
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Article
| Open AccessA cluster-randomized trial of water, sanitation, handwashing and nutritional interventions on stress and epigenetic programming
A regulated stress response is essential for healthy child growth and development. Here, the authors show that a nutrition, water, sanitation, and hygiene intervention enhanced adaptive responses of the physiological stress system in early childhood.
- Audrie Lin
- , Andrew N. Mertens
- & Douglas A. Granger
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Article
| Open AccessAn individualized protein-based prognostic model to stratify pediatric patients with papillary thyroid carcinoma
Papillary thyroid carcinoma has a heterogenous outcome, particularly in paediatric patients. Here, the authors utilise machine learning to create a protein-based prognostic model to predict recurrence risk.
- Zhihong Wang
- , He Wang
- & Yaoting Sun
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Article
| Open AccessLSD1 inhibition circumvents glucocorticoid-induced muscle wasting of male mice
Even though glucocorticoids are potent anti-inflammatory agents, they can cause muscle wasting. Here, the authors show that targeting the glucocorticoid receptor coactivator LSD1 limits muscle loss without reducing the drugs’ efficiency on the immune system.
- Qingshuang Cai
- , Rajesh Sahu
- & Delphine Duteil
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| Open AccessFine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
Here, the authors perform large trans-ancestry fine-mapping analyses identifying large numbers of association signals and putative target genes for colorectal cancer risk, advancing our understanding of the genetic and biological basis of this cancer.
- Zhishan Chen
- , Xingyi Guo
- & Wei Zheng
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| Open AccessMetabolomics facilitates differential diagnosis in common inherited retinal degenerations by exploring their profiles of serum metabolites
Diagnosing inherited retinal degeneration is challenging. This exploratory study showed that metabolomic profiles differ among different subtypes of IRD, and potential biomarkers could be identified to facilitate diagnosis workflow in the near future.
- Wei-Chieh Wang
- , Chu-Hsuan Huang
- & Ta-Ching Chen
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| Open AccessMucosal prime-boost immunization with live murine pneumonia virus-vectored SARS-CoV-2 vaccine is protective in macaques
Immunization via the respiratory route is predicted to increase the effectiveness of SARS-CoV-2 vaccines. Here, Kaiser et al. describe a murine pneumonia virus vectored vaccine expressing spike protein, and show that intranasal immunization of male rhesus macaques provides good mucosal and systemic immunogenicity and efficacy.
- Jaclyn A. Kaiser
- , Christine E. Nelson
- & Cyril Le Nouën
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| Open AccessDiphthamide deficiency promotes association of eEF2 with p53 to induce p21 expression and neural crest defects
Rare disease DEDSSH1-associated DPH1 mutations impair eEF2 diphthamide modification that leads to eEF2 as a transcriptional coactivator for p53 to enhance expression of the cell proliferation inhibitor p21, resulting in birth defects.
- Yu Shi
- , Daochao Huang
- & Weihong Song
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Article
| Open AccessThe airborne transmission of viruses causes tight transmission bottlenecks
Genomic analyses have indicated that a small number of virus particles usually found new infections. Here, the authors use a mathematical model to show that this small transmission bottleneck is a result of the physical processes of airborne virus emission, diffusion, and inhalation.
- Patrick Sinclair
- , Lei Zhao
- & Christopher J. R. Illingworth
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Article
| Open AccessCAR affinity modulates the sensitivity of CAR-T cells to PD-1/PD-L1-mediated inhibition
It has been suggested that targeting the PD-1/PD-L1 axis can increase the anti-tumor properties of chimeric antigen receptor (CAR)-T cells. Here the authors report that CAR affinity modulates the sensitivity of CAR-T cells to PD-1/PD-L1-mediated inhibition.
- Irene Andreu-Saumell
- , Alba Rodriguez-Garcia
- & Sonia Guedan
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| Open AccessSingle-cell analyses reveal transient retinal progenitor cells in the ciliary margin of developing human retina
Formation of the retina during development involves the coordinated action of retinal progenitor cells and their differentiated cell types, which is key for producing a functioning eye. Here the authors provide a detailed atlas of human retinal development, combining scRNA-seq and spatial transcriptomics, and identify key genetic factors that mediate retinal progenitor cell proliferation and differentiation.
- Birthe Dorgau
- , Joseph Collin
- & Majlinda Lako
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| Open AccessLoss of TRIM29 mitigates viral myocarditis by attenuating PERK-driven ER stress response in male mice
Knowledge of pathogenesis mechanisms and effective treatments for viral myocarditis is lacking. Here, Wang et al show that loss of TRIM29 and PERK inhibitor mitigate viral myocarditis by attenuating PERK-driven ER stress and ROS responses in male mice.
- Junying Wang
- , Wenting Lu
- & Junji Xing
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| Open AccessThe gut commensal Blautia maintains colonic mucus function under low-fiber consumption through secretion of short-chain fatty acids
Here, the authors show that elevating fiber intake in humans alters their gut microbiota, which, upon transplantation into mice, enhances intestinal mucus function, and identify a crucial role played by the commensal bacterium Blautia and its fermentation products.
- Sandra M. Holmberg
- , Rachel H. Feeney
- & Bjoern O. Schroeder
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| Open AccessBat-borne H9N2 influenza virus evades MxA restriction and exhibits efficient replication and transmission in ferrets
In this study, the authors report that bat H9N2 influenza A virus replicates and transmits in ferrets, efficiently infects human lung explant cultures, evades MxA antiviral activity in mice, and has low antigenic similarity to seasonal N2, meeting pre-pandemic criteria.
- Nico Joel Halwe
- , Lea Hamberger
- & Martin Beer
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Article
| Open AccessBIN1 knockdown rescues systolic dysfunction in aging male mouse hearts
Cardiac dysfunction is a hallmark of aging in humans and mice. Here, the authors show that by restoring youthful Bridging Integrator 1 (BIN1) protein levels in the hearts of 24-month-old mice in vivo cardiac systolic function is rejuvenated, and the aging phenotype partially reversed within two weeks.
- Maartje Westhoff
- , Silvia G. del Villar
- & Rose E. Dixon
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| Open AccessTravel surveillance uncovers dengue virus dynamics and introductions in the Caribbean
Dengue is a major public health concern in the Americas, and the Caribbean can be a source for reintroduction and spread. Here, the authors use travel surveillance data and genomic epidemiology to reconstruct Dengue epidemic dynamics in the Caribbean from 2009-2022.
- Emma Taylor-Salmon
- , Verity Hill
- & Nathan D. Grubaugh
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| Open AccessAmbient carbon dioxide concentration correlates with SARS-CoV-2 aerostability and infection risk
Carbon dioxide concentration has previously been used as a proxy for overall ventilation efficiency to indirectly estimate the risk of indoor SARS-CoV-2 transmission. Here, authors investigate whether the concentration of carbon dioxide also has a direct mechanistic role in improving transmission efficiency.
- Allen Haddrell
- , Henry Oswin
- & Jonathan P. Reid
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| Open AccessOverlapping Streptococcus pyogenes and Streptococcus dysgalactiae subspecies equisimilis household transmission and mobile genetic element exchange
Streptococcus dysgalactiae subsp. equisimilis is closely related to Streptococcus pyogenes and colonises the same sites in humans. This study examines cross-species transmission interactions and genetic exchange in a high disease burden setting.
- Ouli Xie
- , Cameron Zachreson
- & Steven Y. C. Tong
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| Open AccessLong-term monitoring of SARS-CoV-2 seroprevalence and variants in Ethiopia provides prediction for immunity and cross-immunity
Detailed data on SARS-CoV-2 dynamics in Africa remain limited. Here, the authors use longitudinal serology and SARS-CoV-2 sequencing data from Ethiopia between August 2020 and July 2022 to characterise circulating variants, identify infection pathways, and explore cross-immunity properties.
- Simon Merkt
- , Solomon Ali
- & Andreas Wieser
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| Open AccessWild-type IDH2 is a therapeutic target for triple-negative breast cancer
Isocitrate dehydrogenase (IDH) mutations are associated with cancer development and IDH-mutant inhibitors are approved to treat IDH-mutant cancer. Here, the authors show in preclinical murine models that wild-type IDH2 is a potential therapeutic target for triple-negative breast cancer.
- Jiang-jiang Li
- , Tiantian Yu
- & Peng Huang
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| Open AccessA giant virus infecting the amoeboflagellate Naegleria
This is the first report on a virus infecting the amoeboflagellate Naegleria, including the lethal human pathogen N. fowleri. The new virus isolate, Catovirus naegleriensis (Naegleriavirus, NiV), shows hallmarks of giant viruses (Nucleocytoviricota) and unique adaptations to its protist host.
- Patrick Arthofer
- , Florian Panhölzl
- & Matthias Horn
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| Open AccessLarge-scale cross-ancestry genome-wide meta-analysis of serum urate
This large-scale cross-ancestry genome-wide association study reveals the genetic architecture of serum urate across ancestries and identifies urate-associated diseases and potential targets of urate-lowering drugs.
- Chamlee Cho
- , Beomsu Kim
- & Hong-Hee Won
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Article
| Open AccessLineage specific transcription factor waves reprogram neuroblastoma from self-renewal to differentiation
This study identifies temporal and coordinately regulated cell-state-specific super-enhancers driving the expression of transcription factors that control circuits needed to switch neuroblastoma tumor cells from self-renewal to differentiation.
- Deblina Banerjee
- , Sukriti Bagchi
- & Carol J. Thiele
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| Open AccessThe gut microbiome-prostate cancer crosstalk is modulated by dietary polyunsaturated long-chain fatty acids
Here, using murine models of prostate cancer, the authors show that reduced fecal microbiota alpha-diversity correlates with increased prostate tumor burden, and that Omega-3 prebiotic supplementation reduces prostate cancer up-grading associated with a reduction of gut Ruminococcaceae and fecal butyrate levels.
- Gabriel Lachance
- , Karine Robitaille
- & Vincent Fradet
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| Open AccessAn estrogen receptor α-derived peptide improves glucose homeostasis during obesity
Type 2 diabetes mellitus is an increasing global health issue, which is caused by systemic insulin resistance. Here, the authors show a ligand-independent effect of hepatic ERα in regulating insulin sensitivity and identify an ERα-derived peptide that functions as an insulin sensitizer.
- Wanbao Yang
- , Wen Jiang
- & Shaodong Guo
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| Open AccessClinical associations with a polygenic predisposition to benign lower white blood cell counts
Here, the authors find that a benign polygenic predisposition to lower white blood cell counts is associated with multiple clinical endpoints, suggesting that predisposed individuals are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.
- Jonathan D. Mosley
- , John P. Shelley
- & Vivian K. Kawai
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Article
| Open AccessPD-L1- and IL-4-expressing basophils promote pathogenic accumulation of T follicular helper cells in lupus
Basophils have been implicated in systemic lupus erythematosus (SLE), as evidenced by the fact that basophil-deficient mice do not develop the disease. Here, the authors demonstrate that PD-L1 and IL-4 expression in basophils promotes the pathogenic accumulation of follicular helper T cells in patients with SLE and murine models.
- John TCHEN
- , Quentin SIMON
- & Nicolas CHARLES
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| Open AccessEstimating the effects of temperature on transmission of the human malaria parasite, Plasmodium falciparum
Malaria transmission is affected by temperature but this relationship is not well characterised. Here, the authors experimentally determine the effect of temperature on parasite development in the mosquito and model how it impacts malaria transmission in Kenya under current and future climate scenarios.
- Eunho Suh
- , Isaac J. Stopard
- & Matthew B. Thomas
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| Open AccessMulti-omics analysis reveals COVID-19 vaccine induced attenuation of inflammatory responses during breakthrough disease
Here, Drury et al study gene, microRNA and protein expression during COVID-19, in a randomised controlled trial of ChAdOx1 nCoV19 vaccine and find that ChAdOx1 nCoV-19 attenuates the inflammatory response, thought to be the basis for severe COVID-19.
- Ruth E. Drury
- , Susana Camara
- & Daniel O’Connor
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| Open AccessAn approach to identify gene-environment interactions and reveal new biological insight in complex traits
Here, the authors report 5 loci interacting with smoking/alcohol for serum lipids using a new method akin to Mendelian randomization. They unveil significant heritability through gene-environment interaction and mediation, enhancing understanding of complex trait genetics.
- Xiaofeng Zhu
- , Yihe Yang
- & Hugues Aschard
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Article
| Open AccessBispecific CAR T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: a phase I/II trial
CAR-T cell therapies targeting BCMA have shown promising responses in patients with multiple myeloma (MM), however primary resistance and relapse are frequently observed. Here the authors report the results of a phase I//II study of bispecific CAR T-cells targeting BCMA and CD19 in relapsed/refractory MM.
- Ming Shi
- , Jiaojiao Wang
- & Jiang Cao
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Article
| Open AccessDiet changes due to urbanization in South Africa are linked to microbiome and metabolome signatures of Westernization and colorectal cancer
Here, the authors present a comparative analysis of the diet, microbiome and metabolome of rural and urban Xhosa people in South Africa, associating urban diets with higher abundances of pro-neoplastic microbial metabolites.
- M. C. Ramaboli
- , S. Ocvirk
- & S. J. D. O’Keefe
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Article
| Open AccessAZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation
The hypothalamus is essential for energy regulation, with POMC neurons crucial for controlling food intake and energy balance. Here, the authors show that AZGP1 improves leptin sensitivity in POMC neurons, aiding in weight loss and energy use by altering leptin-JAK2-STAT3 signalling.
- Sheng Qiu
- , Qinan Wu
- & Mengliu Yang
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Article
| Open AccessDeviations in RSV epidemiological patterns and population structures in the United States following the COVID-19 pandemic
Non-pharmaceutical interventions for COVID-19 also impacted the transmission of other viruses including respiratory syncytial virus (RSV). Here the authors describe the changing epidemiology, clinical severity, and genetic diversity of RSV in Chicago, Illinois, from July 2010 to April 2023.
- Estefany Rios-Guzman
- , Lacy M. Simons
- & Judd F. Hultquist
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Article
| Open AccessTAD boundary deletion causes PITX2-related cardiac electrical and structural defects
This study identifies an altered chromatin conformation associated to a cardiac disorder observed in 7 independent families. A deletion of 2 diverging CTCF binding sites on 4q25 induces TAD fusion and leads to PITX2 expression dysregulation.
- Manon Baudic
- , Hiroshige Murata
- & Julien Barc
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Article
| Open AccessAntiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment
Viral infection is a common risk for immune-compromised individuals, particularly pediatric patients receiving hematopoietic stem cell transplants. Here the authors report a phase II trial testing adoptive transfer of third party, virus-specific T cells on the feasibility, safety, clinical responses, as well as homeostasis of antiviral immunity in the recipients.
- Michael D. Keller
- , Patrick J. Hanley
- & Michael A. Pulsipher
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| Open AccessIlluminating the complete ß-cell mass of the human pancreas- signifying a new view on the islets of Langerhans
The pancreatic islets of Langerhans play a pivotal role in regulating blood glucose homeostasis through the regulated secretion of the hormones insulin and glucagon. Here, the authors use deep tissue 3D imaging to re-construct the entire human pancreas at microscopic resolution and display previously unrecognized heterogeneities in the islet’s cellularity with pre-clinical and clinical implications.
- Joakim Lehrstrand
- , Wayne I. L. Davies
- & Ulf Ahlgren
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Article
| Open AccessConsistent survival in consecutive cases of life-supporting porcine kidney xenotransplantation using 10GE source pigs
Xenotransplantation is an imminent clinical reality but concerns remain around the logistics of procurement and the experimental immunosuppression regimens required to achieve long-term xenograft survival. Here the authors show more than 6 month survival of genetically modified porcine kidneys in baboons after regulatory compliant organ procurements, clinically relevant organ preservation times and FDA-approved immunosuppressive reagents.
- Daniel Eisenson
- , Yu Hisadome
- & Kazuhiko Yamada
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| Open AccessAn esophagus cell atlas reveals dynamic rewiring during active eosinophilic esophagitis and remission
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus with unclear immune cell involvement. Here the authors generate a single cell transcriptomic dataset with 400k cells from the esophageal mucosa of active EoE patients, remission EoE patients, and healthy individuals to characterise esophageal cellular composition, phenotype and interaction in this disease.
- Jiarui Ding
- , John J. Garber
- & Ramnik J. Xavier
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Article
| Open AccessMonkeypox virus genomic accordion strategies
The 2023 monkeypox outbreak was caused by a subclade IIb monkeypox virus (MPXV). Here, using advanced sequencing techniques, the authors identify variations on low-complexity regions of the MPXV genome and describe their potential as evolutionary drivers.
- Sara Monzón
- , Sarai Varona
- & Gustavo Palacios