Astrocyte heterogeneity is closely associated with the pathophysiology of traumatic brain injury (TBI), particularly in the development of cerebral edema, which is a major contributor to morbidity and mortality in patients with TBI. However, little is known about how certain astrocyte subpopulations contribute to the development of cerebral edema after acute brain injury. Using multiomics approaches

Atherogenic dyslipidemia and chronic inflammation appear strongly associated with residual cardiovascular disease (CVD) risk. Peroxisome proliferator–activated receptor α (PPARα) agonists, which exert both triglyceride-lowering and anti-inflammatory properties, are potential therapeutic candidates to target residual CVD risk. However, CVD outcome studies with these drugs have yielded mixed results

Liver metastases represent the leading cause of death in patients with colorectal cancer (CRC). Chimeric antigen receptor (CAR) T cell therapy holds promise in this context, but any effort to bring it to the bedside requires careful antigen selection and testing in clinically relevant models. Here, we identified cadherin-17 (CDH17) as a candidate antigen for CAR T cell therapy of CRC liver metastases

Skin-resident regulatory T cells (T reg cells) cells play a critical role in subcutaneous allergen-specific immunotherapy (SIT) for atopic dermatitis (AD). However, a detailed description of the phenotype and origin of skin-resident T reg cells during SIT is lacking. Therefore, we investigated the role and origin of specific T reg lineages in SIT with human AD samples and with a mouse model of AD.

Severe injury accompanied by hemorrhagic shock triggers an early release of cell constituents into the circulation, referred to as the systemic storm. The systemic storm drives the systemic inflammatory response and is associated with increased mortality. The role of programmed cell death (PCD) in the systemic storm was investigated in mice that underwent hemorrhagic shock with tissue trauma (HS/T)

CD4 + CD25 hi FoxP3 + regulatory T cells (T reg cells) are key controllers of immune self-tolerance, and their suppressive function is impaired in people with relapsing-remitting multiple sclerosis (pwRR-MS). Because the mechanisms underlying this condition are still ill-defined, we investigated the role of T reg cell–derived extracellular vesicles (T reg -EVs) in T reg cell dysfunction observed in

Large, randomized trials testing omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplementation to reduce cardiovascular events have reported contradictory results. Interpretation of these trials is challenging, because different dosages and formulations of ω-3 PUFA were tested. Furthermore, the exact mechanisms for the reduction in cardiovascular events are unclear. In this study, we investigated the

Islet transplantation is a promising therapy for insulin-dependent diabetes. However, immune rejection and insufficient vascularization hinder the survival and function of transplanted islets. Here, we show effective engraftment of vascularized and functional mouse and rat islets transplanted into biomaterial-remodeled spleens of nonimmunosuppressed rodents and human islets transplanted into the remodeled

One of the most common sites of cancer metastasis is to the bone. Bone metastasis is associated with substantial morbidity and mortality, and current therapeutic interventions remain largely palliative. Metastasizing tumor cells need to reprogram their metabolic states to adapt to the nutrient environment of distant organs; however, the role and translational relevance of lipid metabolism in bone metastasis

Gonococcus, a bacterium resistant to most antibiotics, causes more than 80 million cases of gonorrhea annually and is considered a high-priority pathogen by the World Health Organization. Recently, vaccine development prospects were boosted by reports that licensed meningococcus serogroup B (MenB) vaccines provided partial protection against gonococcal infection. To determine antigens responsible for

Severe COVID-19 presents with a distinct immunological profile, characterized by elevated neutrophil and reduced lymphocyte counts, seen commonly in fungal and bacterial infections. This study demonstrates that patients hospitalized with COVID-19 show evidence of neutrophil degranulation and have increased expression of neutrophil surface lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1)

Historically, DNA sequence mutability has been considered relatively uniform and low in tumors with chromosomal instability (CIN), based on the assumption that high mutability would be detrimental in karyotypically aberrant contexts. Recent in silico analyses have challenged this view, suggesting some heterogeneity in mutation rates across CIN tumors; however, these predictions lack experimental validation

Neurological disorders with onset before or at birth are a leading cause of morbidity and mortality in infants and children. Prenatal treatment has the potential to reduce or prevent irreversible neuronal loss and facilitate normal neurodevelopment. We hypothesized that antisense oligonucleotides (ASOs) delivered to the amniotic fluid by intra-amniotic (IA) injection could safely distribute to the

Intestinal inflammation continues in a subset of patients with celiac disease despite a gluten-free diet. Here, by applying multi-omic single-cell analysis to duodenal biopsies, we found that low-grade malignancies with lymphoma driver mutations in patients with refractory celiac disease type 2 (RCD2) are comprised by surface CD3-negative (sCD3 − ) lymphocytes stalled at an innate lymphoid cell (ILC)–progenitor

Recent work has shown that prolonged expression of recombinant proteins after adeno-associated virus (AAV)–mediated delivery of gene therapy to long-lived, ventricle-lining ependymal cells can profoundly affect disease phenotypes in animal models of neurodegenerative diseases. Here, we performed in vivo screens of millions of peptide-modified capsid variants of AAV1, AAV2, and AAV9 parental serotypes

There are currently no licensed vaccines for norovirus, a leading cause of epidemic and endemic gastroenteritis worldwide. Clinical advancement of promising vaccine candidates from phase 2 studies to phase 3 field trials has been hampered by the lack of robust immunological correlates of protection. Here, we conducted a phase 2b randomized, placebo-controlled vaccination and challenge study to assess

The abnormal accumulation of misfolded proteins is a common hallmark of many neurodegenerative disorders. Among these proteins, α-synuclein (αsyn) is a well-characterized pathogenic protein in Parkinson’s disease (PD) and other synucleinopathies. αsyn can be hyperphosphorylated and form pathological aggregates, leading to neurodegeneration. Thus, chemical modulators of pathological αsyn may suppress

Treatment of injuries to soft elastic organs is often hindered by challenging anatomical features and limitations of existing sealant materials, which may lack adequate tissue adhesion, elasticity, biocompatibility, and effective hemostatic properties. To address these clinical challenges, we developed an injectable elastic sealant formulated with methacryloyl-modified human recombinant tropoelastin

UBA5 encodes for the E1 enzyme of the UFMylation cascade, which plays an essential role in endoplasmic reticulum (ER) homeostasis. The clinical phenotypes of UBA5 -associated encephalopathy include developmental delays, epilepsy, and intellectual disability. To date, there is no humanized neuronal model to study the cellular and molecular consequences of UBA5 pathogenic variants. We developed and characterized

Poly(ADP-ribose) polymerase inhibitors (PARPis) are a class of agents targeting DNA damage repair that have become standard therapy for epithelial ovarian cancer (EOC) and multiple other solid tumors. In addition to targeting DNA damage repair, PARPis actively modulate antitumor immune responses, with efficacy being partially dependent on T cell activity. Here, we found that patient T cells sustain

After transplantation, inflammation and tissue injury release danger signals that activate myeloid cells, driving adaptive immune responses and acute rejection. Current immunosuppressants primarily target T cells but inadequately control innate immunity. Regulatory signals controlling innate responses in transplantation remain elusive. The sialic acid–binding immunoglobulin-like lectin-E (Siglec-E

The role of splicing dysregulation in cancer is underscored by splicing factor mutations; however, its impact in the absence of such rare mutations remains poorly understood. Prompted by the finding that splicing uniquely resolved genetic subtypes of cancer, we developed an unsupervised computational workflow called OncoSplice to comprehensively define tumor molecular landscapes. In adult and pediatric

Capsular group B meningococcus (MenB) remains an important cause of disease globally, and additional vaccines against MenB would aid in reducing the incidence of infection. Previous work has demonstrated that a MenB adenoviral-vectored vaccine, ChAdOx1 MenB.1, elicited high serum bactericidal responses in preclinical models after a single dose, supporting further clinical development of this vaccine

Determination of a drug’s biodistribution is critical to ensure that it reaches the target tissue of interest. This is particularly challenging in the brain, where invasive sampling methods may not be possible. Here, we present a pretargeted positron emission tomography (PET) imaging methodology that uses bioorthogonal click chemistry to determine the distribution of an antisense oligonucleotide (ASO)

Clones harboring cancer driver mutations can expand in normal tissues, known as somatic mosaicism, and can be influenced by age and environmental and germline factors. Somatic mosaicism in the blood predicts the risk of hematological malignancies; however, the relevance of somatic mosaicism to solid tumors remains unclear, in part because of limited sample availability. Lifestyle habits, including

Hypoglycemic episodes exacerbate diabetic eye disease, which is targetable by dual-HIF inhibition (Guo et al. , this issue).

Luminal organ biopsies are critical for disease diagnosis and are obtained using single-bite forceps inserted through the working channel of large endoscopes. Procedures using these endoscopes frequently require patient sedation or anesthesia and may not be feasible for use in pediatric patients. Additionally, forceps-derived biopsies can suffer from difficulty maintaining tissue orientation, crush

Hypersensitivity, phantom percepts, and sensory reactivity are core features of many neurological disorders. Direct, objective measurements of these features have proven difficult to identify, leaving subjective questionnaires as the primary means of assessing sensory disorder severity. Here, we studied neurotypical adults ( n = 50) or adults with sound sensitivity and tinnitus (ringing of the ears)

Growing genetic and pathological evidence has identified microglial dysfunction as a key contributor to the pathogenesis and progression of various neurological disorders, positioning microglia replacement as a promising therapeutic strategy. Traditional bone marrow transplantation (BMT) methods for replenishing brain microglia have limitations, including low efficiency and the potential for brain

The blood-retinal barrier (BRB) serves as a physiological boundary regulating the passage of nutrients, waste, ions, proteins, and water to and from the retina. In patients with diabetic retinopathy, breakdown of the inner BRB (iBRB) results in damage to the neurovascular unit and is a principal cause of vision loss in the diabetic population. Here, we demonstrate that hypoglycemia, a common consequence

Messenger RNA (mRNA) has emerged as a highly effective and versatile platform for vaccine delivery. We previously designed a virus-like particle (VLP)–forming env-gag mRNA vaccine against human immunodeficiency virus–1 (HIV-1) that elicited envelope-specific neutralizing antibodies and protection from heterologous simian-human immunodeficiency virus (SHIV) infection in rhesus macaques. Here, we introduce

Calciphylaxis is an orphan disease characterized by dermal microvessel thrombosis, inflicting painful cutaneous necrosis. It occurs predominantly in patients with end-stage kidney disease and has high mortality, elusive pathogenesis, and no approved therapies. We demonstrate that sera from patients with calciphylaxis induced de novo synthesis of interleukin-6 (IL-6) and soluble IL-6 receptor (IL-6R)

Lyme disease, caused by Borrelia burgdorferi in the United States, is an escalating human health problem that can cause severe disease if not properly treated. Doxycycline is the primary treatment option for Lyme disease; however, several concerns are associated with high-dose doxycycline treatment. For example, doxycycline is a broad-spectrum antibiotic and kills beneficial bacteria. Doxycycline is

Persistent symptoms after an acute infection is an emerging public health concern, but the pathobiology of such conditions is not well understood. One possible scenario involves the persistence of lingering antigen. We have previously reported that patients with postinfectious Lyme arthritis often harbor the peptidoglycan (PG) cell wall of Borrelia burgdorferi , the Lyme disease agent, in the synovial

Chronic wounds are a major global health challenge associated with substantial economic burden and a negative impact on patient quality of life. Real-time analysis of biomarkers like reactive oxygen and nitrogen species could guide treatment, but existing systems lack the capacity required for continuous monitoring. Wound exudate is secreted slowly and has a complex composition, making efficient fluid

Genome-wide association studies (GWASs) have identified more than 1000 loci where genetic variants correlate with kidney function. However, the specific genes, cell types, and mechanisms influenced by these genetic variants remain largely uncharted. Here, we identified glutathione-specific gamma–glutamylcyclotransferase 1 ( CHAC1 ) on chromosome 15 as affected by GWAS variants by analyzing human kidney

Antibodies mediate protection against a wide range of pathogens through binding and neutralizing the pathogen or through Fc-mediated effector functions. Human monoclonal antibodies (mAbs) CIS43LS and L9LS show high-affinity binding targeting distinct regions on the Plasmodium falciparum circumsporozoite protein (PfCSP) and are highly effective in preventing malaria in humans. However, the role of FcγR

Current asthma treatments manage disease symptoms but fail to address the underlying cause of allergic disease. Allergen immunotherapy holds the promise for durable disease control by establishing allergen-specific tolerance through repeated introduction of native allergens; however, its efficacy can be limited by long interventions, reactions upon administration, and poor patient compliance. Here

Dose-limiting toxicities remain a major barrier to drug development and therapy, revealing the limited predictive power of human genetics. Here, we demonstrate the utility of a more comprehensive approach to studying drug toxicity through longitudinal profiling of the human gut microbiome during colorectal cancer (CRC) treatment (NCT04054908) coupled to cell culture and mouse experiments. Substantial

Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder caused by the expansion of a CTG-triplet repeat in the 3′ untranslated region of the dystrophia myotonica protein kinase ( DMPK ) gene. It results in the transcription of toxic RNAs that contain expanded CUG repeats (CUG exp ). Splicing factors, such as muscleblind-like 1 (MBNL1), are sequestered by CUG exp , thereby disrupting

Cellular prion protein (PrP C ), known for its pathological isoform in prion diseases such as Creutzfeldt-Jakob disease, is primarily expressed in the nervous system but has also been detected in the blood and urine of individuals with renal dysfunction. However, the role of PrP C in the development of renal disease is unexplored. Here, we showed that PrP C was up-regulated in fibrotic renal lesions

Artificial intelligence (AI) has already transformed vaccine antigen design and could transform the entire vaccinology pipeline, including immune responses and emerging infectious disease prediction, manufacturing and regulatory processes, clinical trial design and implementation, and vaccine access and equity. However, realizing the promise of AI for vaccinology requires more high-quality data.

Patients with relapsed/refractory (r/r) T cell acute lymphoblastic leukemia (T-ALL) have a dismal prognosis, highlighting the urgent need for effective therapies. Chimeric antigen receptor (CAR)–T cell approaches targeting pan–T cell antigens may be limited by T cell aplasia and fratricide, necessitating “rescue” allogeneic hematopoietic stem cell transplantation. In this study, we identify CD21, a

The tumor microenvironment predominantly polarizes tumor-associated macrophages (TAMs) toward an M2-like phenotype, thereby inhibiting antitumor immune responses. This process is substantially affected by metabolic reprogramming; however, reeducating TAMs to enhance their antitumor capabilities through metabolic remodeling remains a challenge. Here, we show that tumor-derived microparticles loaded

Immune checkpoint blockade (ICB) has revolutionized cancer treatment; however, many patients develop therapeutic resistance. We previously identified and validated a pretreatment peripheral blood biomarker, characterized by a high frequency of LAG-3 + lymphocytes, that predicts resistance in patients receiving anti–PD-1 (aPD-1) ICB. To better understand the mechanism of aPD-1 resistance, we identified

Nuclear retroelement transcripts (RTs), which can be elicited both transcriptionally and posttranscriptionally, form double-stranded RNA (dsRNA) in cytosol to trigger the viral mimicry response (VMR) and antitumor immunity. However, the strength of the induced VMR varies tremendously across tumor types, and the underlying mechanisms remain poorly understood. Here, we demonstrate that the mRNA export

Rapid portable assays are needed to improve diagnosis, treatment, and reduce transmission of tuberculosis (TB), but current tests are not suitable for patients in resource-limited settings with high TB burden. Here we report a low complexity, lab-in-tube system that is read by an integrated handheld device that detects Mycobacterium tuberculosis ( Mtb ) DNA in blood and respiratory samples from a variety

Organ fibrosis causes major morbidity and mortality worldwide. Treatments for fibrosis are limited, with organ transplantation being the only cure. Here, we review how various state-of-the-art spatial genomics approaches are being deployed to interrogate fibrosis across multiple organs, providing exciting insights into fibrotic disease pathogenesis. These include the detailed topographical annotation

Kidney fibrosis determines clinical outcomes in individuals with chronic kidney disease (CKD). The stoichiometric ratio of collagens in renal scar differs from that of healthy kidney extracellular matrix (ECM), but the functional importance of altered collagen types in injured kidneys remains unclear. Using human population studies, we show that circulating protein and renal mRNA amounts of collagen

Identification of GDF15 as a cause of severe nausea and vomiting during pregnancy is opening new doors for treatment and prevention.

Conventional methods of gene transfer lead to inconsistent transgene expression within cells. This variability can be problematic, particularly in conditions like Rett syndrome (RTT), a neurological disorder caused by mutations in the MECP2 (methyl-CpG binding protein 2) gene, because overexpression of MECP2 can also cause adverse effects. To address these challenges, we devised a gene regulation system

Human pluripotent stem cell–derived islet (SC-islet) transplantation is a promising β cell replacement therapy for patients with type 1 diabetes, offering a potential unlimited cell supply. Yet, the heterogeneity of the final cell product containing non–target cell types has relevant implications for SC-islet function, transplant volume, and cell product safety. Here, we present a clinically compliant

Reproducing the pathophysiology of human multiple sclerosis (MS) in animal models is critical to identifying mechanisms triggering demyelination and to developing early intervention strategies. Here, we aimed to model overactivated Wnt (wingless-related integration site) signaling previously shown in postmortem brain tissues of patients with MS by inducing experimental autoimmune encephalomyelitis

The number of patients requiring dialysis therapy continues to increase worldwide because of the lack of effective treatments for chronic kidney disease (CKD). Furthermore, no curative treatments for acute kidney injury (AKI) have been established. The therapeutic effects of human induced pluripotent stem cell–derived nephron progenitor cells (hiPSC-NPCs) on AKI have been reported in mice but not clinically

Metabotropic glutamate receptor 5 (mGluR5) is involved in cocaine reward processing and addiction. Preclinical studies suggest that blocking this receptor inhibits cocaine self-administration and seeking behavior in rodents. We assessed a selective noncompetitive antagonist of mGluR5 called mavoglurant in a phase 2 randomized, placebo-controlled clinical trial of 68 adults with cocaine use disorder

The Janssen Ebola virus (EBOV) vaccine consists of the adenovirus type 26 vector encoding the EBOV glycoprotein (GP) (Ad26.ZEBOV) and the modified vaccinia Ankara (MVA) vector encoding GP from EBOV, Sudan virus, and Marburg virus and nucleoprotein from Tai Forest virus (MVA-BN-Filo) administered 8 weeks later. We conducted a systems immunology analysis of antibody-mediated and cellular immune responses