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| Open AccessPostmortem imaging reveals patterns of medial temporal lobe vulnerability to tau pathology in Alzheimer’s disease
Using high-resolution ex vivo MRI and serial histology, Ravikumar et al. characterise 3D tau spread across histologically defined medial temporal lobe subregions thus providing a postmortem reference for in vivo studies on early Alzheimer’s disease.
- Sadhana Ravikumar
- , Amanda E. Denning
- & Paul A. Yushkevich
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Article
| Open AccessOrthogonal proteogenomic analysis identifies the druggable PA2G4-MYC axis in 3q26 AML
The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia subgroup carrying 3q26 abnormalities. Here, pan-histone deacetylase inhibitors are identified as potent repressors of EVI1 and PA2G4 as a druggable target.
- Matteo Marchesini
- , Andrea Gherli
- & Giovanni Roti
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| Open AccessLongitudinal multicompartment characterization of host-microbiota interactions in patients with acute respiratory failure
Here, the authors profile the oral, lung, and gut microbiota of 479 patients with acute respiratory failure, revealing that reduced diversity and increased pathogen presence can predict survival outcomes, highlighting the potential for microbiota-based approaches in critical care.
- Georgios D. Kitsios
- , Khaled Sayed
- & Bryan J. McVerry
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| 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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| 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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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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| 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 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 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 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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| 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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| 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 AccessMedical history predicts phenome-wide disease onset and enables the rapid response to emerging health threats
Preventive interventions often require strategies to identify high-risk individuals. Here, the authors illustrate the potential utility of medical history in predicting the onset risk for thousands of diseases across clinical specialties including COVID-19.
- Jakob Steinfeldt
- , Benjamin Wild
- & Roland Eils
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Article
| Open AccessAI-enhanced integration of genetic and medical imaging data for risk assessment of Type 2 diabetes
Type 2 diabetes is a global health threat demanding precise healthcare methods. Here, the authors show that their AI-driven risk assessment models, integrating genetic, imaging, and demographic data, achieve high accuracy in identifying high-risk groups, promising advancements in prevention strategies.
- Yi-Jia Huang
- , Chun-houh Chen
- & Hsin-Chou Yang
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Article
| Open AccessEnhancing in vivo cell and tissue targeting by modulation of polymer nanoparticles and macrophage decoys
Targeted drug delivery in vivo is a complex challenge, and understanding the characteristics that define the behavior of delivery vehicles in vivo is vital for advancing delivery vehicle design. Here the authors use a library of polymeric delivery vehicles and high-throughput tools to study the structure-function relationships guiding the physiological fate of nanomedicines.
- Alexandra S. Piotrowski-Daspit
- , Laura G. Bracaglia
- & W. Mark Saltzman
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| Open AccessOriginal COVID-19 priming regimen impacts the immunogenicity of bivalent BA.1 and BA.5 boosters
Waning immunity and the emergence of the SARS-CoV-2 Omicron lineage led to reduced vaccine effectiveness and required vaccine updates. Here, the authors assess how different priming regimens affect the immunogenicity of BA.1 and BA.5 bivalent boosters.
- Luca M. Zaeck
- , Ngoc H. Tan
- & Rory D. de Vries
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| Open AccessFOXC1 regulates endothelial CD98 (LAT1/4F2hc) expression in retinal angiogenesis and blood-retina barrier formation
FOXC1 transcription factor plays a role in vascular development, but its mechanism is not well defined. Here, the authors show FOXC1 regulates retinal angiogenesis by promoting CD98 amino acid transporter expression to activate mTOR signalling, and also by promoting blood-retina barrier formation.
- Teena Bhakuni
- , Pieter R. Norden
- & Tsutomu Kume
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| Open AccessComparison of intramyocellular lipid metabolism in patients with diabetes and male athletes
Endurance athletes and sedentary type 2 diabetes patients swapped their lifestyle for 8 weeks. Athletes store and utilise saturated fat intensely for performant physical activity, and type 2 diabetes patients reversed their dysmetabolic lipid state after endurance training.
- Alice M. Mezincescu
- , Amelia Rudd
- & Dana Dawson
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| Open AccessA burden of proof study on alcohol consumption and ischemic heart disease
Alcohol use is commonplace and ischemic heart disease (IHD) the leading cause of death globally, yet their relationship is unclear. Here we show that study type determines whether research finds alcohol reduces IHD risk or is unrelated, arguing for new approaches to settle this critical debate.
- Sinclair Carr
- , Dana Bryazka
- & Emmanuela Gakidou
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| 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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| 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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| Open AccessAssessment of three antibiotic combination regimens against Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries
High levels of extended spectrum beta-lactamase (ESBL) and carbapenemase encoding genes were detected in bacterial isolates causing neonatal sepsis in LMICs. Authors assess the in vitro activity of three antibiotics (fosfomycin, flomoxef and amikacin) in combination against ESBL-producing Klebsiella pneumoniae and Escherichia coli isolates.
- Biljana Kakaraskoska Boceska
- , Tuba Vilken
- & Herman Goossens
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| Open AccessThe pan-PPAR agonist lanifibranor improves cardiometabolic health in patients with metabolic dysfunction-associated steatohepatitis
Cardiovascular events are the main cause of mortality in patients with metabolic dysfunctionassociated steatohepatitis (MASH). Here, the authors show that lanifibranor improves cardiometabolic health - insulin sensitivity, lipid and glucose metabolism, systemic inflammation and hepatic steatosis.
- Michael P. Cooreman
- , Javed Butler
- & Sven M. Francque
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Article
| Open AccessSputum culture reversion in longer treatments with bedaquiline, delamanid, and repurposed drugs for drug-resistant tuberculosis
In patients with drug-resistant tuberculosis who receive treatment with new and repurposed drugs, indicators of advanced disease and delayed conversion were associated with an increased risk of reversion. These factors may be targets for close monitoring.
- Sooyeon Kho
- , Kwonjune J. Seung
- & Molly Franke
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| Open AccessCharacterizing the mechanism of action for mRNA therapeutics for the treatment of propionic acidemia, methylmalonic acidemia, and phenylketonuria
mRNA therapeutics delivered via lipid nanoparticles are being developed for the treatment of metabolic diseases caused by protein deficiency. Here, the authors use preclinical data to develop translational PK/PD models, which scaled allometrically to humans to predict starting doses for first-in-human clinical studies for in propionic acidemia, methylmalonic acidemia, and phenylketonuria.
- Rena Baek
- , Kimberly Coughlan
- & Paolo G. V. Martini
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| 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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Article
| Open AccessGenetic association of inflammatory marker GlycA with lung function and respiratory diseases
Here, the authors observed significant genetic correlation of GlycA with lung function, asthma and COPD and identified ten shared loci revealing potential shared biological mechanisms involving ubiquitination and Wnt/β-catenin signaling.
- Yanjun Guo
- , Quanhong Liu
- & Weihong Chen
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Article
| Open AccessCirculating fatty acids and risk of hepatocellular carcinoma and chronic liver disease mortality in the UK Biobank
Different fatty acids have been associated to liver diseases. Here, the authors show that plasma levels of different circulating fatty acids are either negatively or positively associated with the risk of hepatocellular carcinoma and chronic liver disease mortality in the UK Biobank cohort.
- Zhening Liu
- , Hangkai Huang
- & Chengfu Xu
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Article
| Open AccessUsing genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes
Here, the authors integrate genomic and transcriptomic data obtained from African-ancestry female participants and identify six genes associated with breast cancer risk which provides biological insights into this common cancer in an underrepresented population.
- Jie Ping
- , Guochong Jia
- & Wei Zheng
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Article
| Open AccessA patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesis
Most people affected by Alcohol Use Disorder do not develop cirrhosis. Here, the authors show that induced pluripotent stem cell-derived hepatocytes from patients with Alcohol Cirrhosis, have impaired cell energy production and were more susceptible to oxidative stress, which is partially reversed by treatment with Aramchol.
- Bani Mukhopadhyay
- , Cheryl Marietta
- & David Goldman
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| Open AccessDevelopment of Aptamer-DNAzyme based metal-nucleic acid frameworks for gastric cancer therapy
The development of metal-nucleic acid nanocomposites for therapeutic is limited by poor stability and synthesis efficiency. Here, the authors develop a multi-fragmented aptamer DNAzyme metal-nucleic acid frameworks (MNFs) under milder conditions and demonstrate its preclinical efficacy in gastric cancer.
- Jiaqi Yan
- , Rajendra Bhadane
- & Hongbo Zhang
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| Open AccessPrimary prophylaxis with mTOR inhibitor enhances T cell effector function and prevents heart transplant rejection during talimogene laherparepvec therapy of squamous cell carcinoma
Cutaneous squamous cell carcinoma is more frequent and more aggressive in the organ transplanted and represent a therapeutic challenge due to the ongoing transplantrelated immune suppression. Here, the authors present a case report of a patient whose T cell responses were successfully strengthened via primary prophylactic therapy with mammalian target of rapamycin inhibition and intra-lesion injection of the oncolytic herpesvirus T-VEC.
- Victor Joo
- , Karim Abdelhamid
- & Michel Obeid
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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 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 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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Article
| 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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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 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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Article
| 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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Article
| 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 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 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 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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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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Article
| Open AccessMalnutrition enteropathy in Zambian and Zimbabwean children with severe acute malnutrition: A multi-arm randomized phase II trial
Childhood malnutrition in Africa is a glaring example of global inequality, and mortality remains high. Here, the authors report the results of the TAME randomized phase II clinical trial, in which intestinal healing was the target of four potential interventions in malnourished children in Zambia and Zimbabwe.
- Kanta Chandwe
- , Mutsa Bwakura-Dangarembizi
- & Paul Kelly
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Article
| Open AccessPerinatal outcomes after admission with COVID-19 in pregnancy: a UK national cohort study
The impacts of maternal SARS-CoV-2 infection on newborns are not well understood. Here, the authors perform a national cohort study using data on births in the UK from March 2020—March 2022 and find that moderate to severe maternal COVID-19 was associated with adverse perinatal outcomes.
- Hilde Marie Engjom
- , Rema Ramakrishnan
- & Marian Knight
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| Open AccessDonor regulatory T cells rapidly adapt to recipient tissues to control murine acute graft-versus-host disease
Graft-versus-Host disease is a major complication after allogeneic bone marrow transplantation and is ameliorated by adoptively transferred donor regulatory T cells. Here, the authors apply transcriptomic and TCR profiling to assess regulatory T cell organ-specific adaptation in murine bone marrow transplantation models.
- David J. Dittmar
- , Franziska Pielmeier
- & Michael Rehli
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Article
| Open AccessInfluenza antibody breadth and effector functions are immune correlates from acquisition of pandemic infection of children
In this study, the authors assessed influenza-specific antibody responses in a cohort of seasonally vaccinated children and report that seasonal vaccination is beneficial by enhancing pandemic influenza virus-specific antibodies and cross-reactive effector functions.
- Janice Z. Jia
- , Carolyn A. Cohen
- & Sophie A. Valkenburg