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A comprehensive atlas platform integrating transcriptional and epigenetic data enables more precise engineering of T cell states, accelerating the rational design of more effective cellular immunotherapies.

Cosgun et al. show that, in B cell leukemia, β-catenin expression is maintained at low levels through glycogen synthase kinase 3B (GSK3β)-mediated phosphorylation. Inhibition of GSK3β results in β-catenin–Ikaros–NuRD complex formation, leading to B-ALL cell death through MYC repression.

Allogeneic T cell therapies could be used in therapeutic applications because of their potential for ‘off-the-shelf’ access and standardised production. Here the authors have developed a multidimensional workflow profiling platform for EBV-specific T cell therapy and show that correlative biomarkers of T cell potency and effector function are associated with therapeutic effectiveness in xenogeneic mouse EBV-LCL models.

Evidence from trials suggests SARS-CoV-2 binding antibody thresholds could serve as surrogate markers of neutralising capacity, but whether this is accurate in the context of variants of concerns, or in the event of prior infection or vaccination remains unclear. Authors explore the performance of receptor binding domain IgG thresholds in predicting a level of neutralising capacity that has demonstrated protection against infection in vaccine trials

In a trial involving 45 clinics and 15,596 visits, the use of an AI-based screening tool applied to ECG for opportunistic detection of advanced chronic liver disease led to a significant increase in new diagnoses compared to the standard workflow.

Adjuvants are an important component of modern vaccines. Here, the authors employ a phenotypic screen of ~200k compounds and identify PVP-057, a TLR3 agonist with a simple scalable 3-step synthesis, as an adjuvant that induces durable humoral and cellular immunity to varicella-zoster virus (VZV) gE in mice.

Interferon-ε is a tumour suppressor expressed in the epithelial cell of origin of ovarian cancer, which it restricts by direct action on tumour cells and especially by activation of anti-tumour immunity.

Exploiting the high abundance of mutant p53 protein, a small molecule was developed that specifically binds to p53-Y220C mutants and delivers a mitosis blocker, killing TP53-mutant cancer cells while sparing healthy ones.

This study explores the impact of mood and individual differences on trading off between possible rewards and checking for the presence for threat and escaping to safety in a gamified foraging task.

Engineered DNA recombinases efficiently and specifically insert genetic cargos without the use of landing pads.

Galsky and colleagues report the results of a phase 1 clinical trial of anti-programmed cell death protein 1 ligand 1 atezolizumab in combination with PGV001, a personalized neoantigen vaccine, in participants with urothelial cancer.

Surgical menopause occurs in premenopausal women who undergo radical cystectomy with bilateral oophorectomy to treat bladder cancer. This Review discusses the pathophysiology of surgical menopause in these patients and highlights current strategies to mitigate associated symptoms and long-term health risks.

SOCS1 is a potent suppressor of JAK-STAT signalling responses to IFNγ and γ-chain cytokines and thereby limits inflammation. Here the authors identify and characterize heterozygous SOCS1 mutations in 10 patients from 5 unrelated families with autoimmune diseases.

Savan and colleagues show that distinct isoforms of the RNA-binding protein ZAP function as an antiviral restriction factor or as an interferon-resolution factor, based on differences in their intracellular localization.

Herpesvirales utilize a unique nuclear egress route for capsid export. Here the authors show that herpesviruses exploit a cellular membrane protein, once thought to transport chloride, to facilitate membrane fusion and egress from the nucleus.

The beta variant (B.1.351) is to date the most resistant to neutralization of the SARS-CoV-2 variants. Using nonhuman primates, Seder and colleagues demonstrate that double vaccination with a high dose of the lipid nanoparticle vaccine mRNA-1273 protects against infection with the beta variant.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

A CRISPR knock-in strategy that uses endogenous gene regulatory mechanisms can engineer ‘armoured’ CAR T cells that secrete proinflammatory cytokines directly within a tumour without causing toxicity, leading to prolonged survival in mice.

This study explores the relationship between telomere length and clonal hematopoiesis. Splicing factor and PPM1D gene mutations are more frequent in people with genetically predicted shorter telomere lengths, suggesting that these mutations protect against the consequences of telomere attrition.

This study presents a large-scale enhancer screening approach to optimize gene therapy vectors. A compact, potent, erythroid-specific enhancer used in a therapeutic vector, improved viral titers, transducibility, and restored hemoglobin levels in β-thalassemia patient-derived cells.

Structural and functional studies of Zinc finger antiviral protein and its cofactors, TRIM25 and KHYNYN, reveal the formation of complexes and suggest that multivalent recognition of CpG-rich RNA targets it for nucleolytic depletion.

During SARS-CoV-2 infection caspase-8 fuels harmful inflammation independent of apoptosis. Genetic loss of caspase-8 reduces cytokine levels, lowers viral load and mitigates disease severity, revealing non-apoptotic caspase-8 as a key driver of severe COVID-19.

Here, the authors report results from a Phase 1 trial with an AS03-adjuvanted, plant-based virus-like particle displaying the spike protein of the ancestral SARS-CoV-2. Six months post-second dose, they observe good neutralizing antibody titers and T cell responses to ancestral virus and variants of concern in participants.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

α/β-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase, and its expression in CD4 + T-cells has been linked to remission status in rheumatoid arthritis. Here the authors report that pharmacological inhibition of ABHD11 modulates T-cell effector function via increased 24,25-epoxycholesterol biosynthesis and subsequent liver X receptor activation.

A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

Reliance on text supervision for biomedical image encoders is investigated. The proposed RAD-DINO, pretrained solely on unimodal data, achieves similar or greater performance than state-of-the-art multimodal models on various benchmarks.

Sadhu et al. identify and functionally validate ferredoxin-1 (FDX1) as a determinant of cholesterol metabolism and cardiovascular risk in Asian populations.

Defined levels of SARS-CoV-2-specific binding and neutralizing antibodies elicited by the COVID-19 vaccine ChAdOx1 nCoV-19 are identified as correlates of protection against symptomatic infection.

There are currently no good ways to track human cells in vivo in a clinical setting using magnetic resonance imaging (MRI) based on superparamagnetic iron-oxide nanoparticles. Mya Thu and colleagues have introduced a simple magnetic cell labeling approach that combines three currently US Food and Drug Administration–approved drugs—ferumoxytol, heparin and protamine—to form self-assembling nanocomplexes of about 150 nm in size that effectively label cells for MRI. The approach was shown to effectively label three types of stem cells and two types of immune cells.

Brucellosis is a zoonotic disease with high prevalence in the Middle East. Here the authors identify camels as an important source of brucellosis among livestock-owning households in Jordan, due to widespread consumption of raw camel milk.

This Resource describes data, code and tools developed for the Human Reference Atlas and the Human BioMolecular Atlas Program for building and navigating a multiscale human atlas.

Monitoring T cell metabolism during chimeric antigen receptor T manufacturing using optical metabolic imaging enables fine-tuning of manufacturing conditions to increase T cell yield and fitness.

Hypoimmune gene editing in human pluripotent stem cells (hPSCs) provides a promising platform for cellular therapies. Here, the authors report that CRISPR mediated deletion of ICAM-1 in hPSC-derived grafts reduces immune cell adhesion, dampens T cell activation, and protects against immune rejection.

Impaired NAD⁺ biosynthesis may be a common feature of high-risk hospitalizations for which NAD⁺ augmentation could improve therapeutic outcome.

Vectors used in gene therapy for hemoglobin disorders carry globin in a reverse-orientation to prevent the loss of key regulatory elements by RNA splicing, but this limits their efficiency. Here, the authors develop a vector carrying β-globin in a forward orientation and show that it has improved titers and transduction efficiency in humanized mice and nonhuman primates.

UCN2 acts as a ligand for the GPCR CRHR2 and there have been conflicting reports on whether UCN2 treatment improves or worsens glucose tolerance. Here, the authors show that acute UCN2 recruits Gs and decreases glucose uptake, while chronic treatment desensitizes CRHR2 and improves glucose uptake.

Vaccines with broad and long-lasting protection against variants of concern are still limited. Here, the authors report a self-amplifying RNA (saRNA) vaccine expressing a membrane-anchored SARS-CoV-2 Spike RBD and show that it elicits broad, durable and protective immunity in small animal models and NHPs.

Federated learning (FL) algorithms have emerged as a promising solution to train models for healthcare imaging across institutions while preserving privacy. Here, the authors describe the Federated Tumor Segmentation (FeTS) challenge for the decentralised benchmarking of FL algorithms and evaluation of Healthcare AI algorithm generalizability in real-world cancer imaging datasets.

Adoptive T-cell immunotherapy offers promise to patients who are resistant to standard anti-viral strategies. Here the authors describe clinical observations in patients with viral complications treated with adoptive immunotherapy over the last 15 years.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

Glucagon plays a key role in regulating blood glucose levels. Here, Liu et al. show that

activation of α-cell Gs signaling promotes the release of glucagon from pancreatic islets and ensures the synthesis of sufficient amounts of glucagon.

In a phase 2 randomized control trial, intermittent senolytic therapy administered to postmenopausal women did not result in a reduction in the bone resorption marker, serum CTx, compared to control at 20 weeks.

Vaccination provides protection from COVID-19, but optimization in design and route is an ever-ongoing process. Here the authors pursue an open-label, multi-arm phase I clinical trial to report the safety of a multi-valent, aerosol vaccine administered via inhalation, as well as superior mucosal immunity induced by ChAd over HuAd vectors.

Langerhans cells (LC) can prime tolerogenic as well as immunogenic responses in the skin. Here the authors show, by transcriptomic, epigenetic and CRISPR editing analyses, that during LC migration and maturation the transcription factor IRF4 regulates expression of antigen presentation and co-stimulatory gene modules while attenuating inflammatory response genes.

A CRISPR-Cas9 approach is used to perform saturating mutagenesis of the human and mouse BCL11A enhancers, producing a map that reveals critical regions and specific vulnerabilities; BCL11A enhancer disruption is validated by CRISPR-Cas9 as a therapeutic strategy for inducing fetal haemoglobin by applying it in both mice and primary human erythroblast cells.