Issues

Judy Lieberman is a professor of pediatrics and adjunct professor of genetics at Harvard Medical School and an endowed chair in cellular and molecular medicine. Her lab studies cytotoxic T lymphocytes (CTL), key cells in the immune defense against viral infection and cancer, as well as molecular pathways activated by the granzymes, and how RNA interference (RNAi) regulates cell differentiation in health and disease states.

In this issue of the Journal of Experimental Medicine, Cao et al. demonstrate that the connection between the eye and the brain goes beyond the impulses carried by the optic nerve and that in Alzheimer’s disease (AD), the influx of toxic Aβ from the brain to the retina underlies AD-induced retinal degeneration.

Rosain et al. describe the association between anti-type I interferon autoantibodies and severe viral infections in patients with incontinentia pigmenti and heterozygous loss-of-function NEMO variants, suggesting a role for canonical NF-κB signaling in immune tolerance.

Niels Bovenschen and colleagues showcase a community-engaged and challenge-based educational concept at Utrecht University, the Netherlands, in which undergraduate students conduct transdisciplinary research on authentic complex biomedical problems.

This review describes the current state of understanding of how RNA processing is dysregulated in cancer (including alterations in RNA splicing, capping, polyadenylation, and decay) and how this knowledge is being harnessed for therapeutic intent.

Following over two decades of clinical success for anti-TNF drugs, antagonists against multiple TNF/TNFR superfamily proteins are in development for IMIDs. This review explores the promise of these signaling molecules and highlights the opportunities and challenges in this fast-evolving area.

Tam et al. report that a lymphoma-associated gain-of-function GPR34 variant promotes immune cell accumulation in the peritoneal cavity and demonstrate that this accumulation requires the lysophosphatidylserine-generating enzyme PLA1A.

The article identifies a direct connection between the brain and the eyes where Aβ from the brain can be transported to the eyes via the brain–eye pathway, leading to Alzheimer’s disease retinopathy.

Heterozygosity for null NEMO mutations underlies hypotrophic and dysplastic thymus in mice and humans. Women with incontinentia pigmenti therefore have a high prevalence of autoantibodies neutralizing type I interferons, which predisposes them to severe viral diseases.

Lubin, Patel, Mackerodt, and colleagues define the circulating lifespan of conventional human dendritic cells (cDC) at steady state. They show that local inflammation recruits cDC to the site of inflammation, where Axl Siglec-6 DC (ASDC) acquires an effector phenotype.

This study demonstrates that early initiation of ART enhances immune selection pressure on HIV-1 reservoir cells and accelerates the accumulation of intact proviruses in heterochromatin regions; phenotypic profiling of reservoir cells suggests that these effects are primarily driven by innate immunity.

B cells undergo extensive genomic reorganization during their proliferation and differentiation into germinal center and antibody-secreting cells. Stoler-Barak et al. demonstrate that SMARCA5, a component of the ISWI-complex, plays a critical role in gene accessibility and expression, facilitating the antibody-mediated immune response.

This work reveals the crucial role of impaired mitochondrial function in pulmonary angiogenesis deficiency, a key factor in the mortality of pulmonary arterial hypertension (PAH) patients. Chronic lipoic acid supplementation improves mitochondrial function, prevents angiogenic deficiency, and may offer a promising therapeutic option.

Hsu et al. report the crosstalk between inositol and purine metabolism via IMPA1/inositol/IMPDH2 axis as a key mechanism for maintaining AR^low/− PCSC properties, which leads to CRPC progression and ABT resistance.

This study reveals a previously undiscovered connection between the inhibition of telomerase/telomere and the therapeutic efficacy of osimertinib. Cotargeting telomerase/telomere is a potential strategy for managing acquired resistance to osimertinib or other third-generation EGFR inhibitors that warrants further clinical evaluation.

Pancreatitis promotes KRAS independence through TGFβ signaling. NFAT5 acts as a critical co-factor for SMAD3 and SMAD4 in driving TGFβ-induced epithelial-to-mesenchymal transition and resistance to KRAS-targeted therapy in pancreatic cancer.