Orchestrating a viral takeover: For some pathogenic viruses, outbreaks occur when a new viral strain emerges and displaces the endemic strain. How such a takeover occurs at a molecular level, however, remains an open question. Manokaran et al. examined one example, the emergence of a new clade of dengue virus (DENV) that caused an outbreak in Puerto Rico in 1994. The epidemic strain produced elevated amounts of subgenomic flavivirus RNA (sfRNA), a viral noncoding RNA, relative to amounts of genomic viral RNA. sfRNA bound to and inhibited TRIM25, a protein important for activating the host's antiviral response, and so by reducing host immunity was able to increase its own fitness. Science , this issue p. 217

Diabetes is associated with activation of the polyol pathway, in which glucose is converted to sorbitol by aldose reductase. Previous studies focused on the role of sorbitol in mediating diabetic complications. However, in the proximal tubule, sorbitol can be converted to fructose, which is then metabolized largely by fructokinase, also known as ketohexokinase, leading to ATP depletion, proinflammatory cytokine expression, and oxidative stress. We and others recently identified a potential deleterious role of dietary fructose in the generation of tubulointerstitial injury and the acceleration of CKD. In this study, we investigated the potential role of endogenous fructose production, as opposed to dietary fructose, and its metabolism through fructokinase in the development of diabetic nephropathy. Wild-type mice with streptozotocin-induced diabetes developed proteinuria, reduced GFR, and renal glomerular and proximal tubular injury. Increased renal expression of aldose reductase; elevated levels of renal sorbitol, fructose, and uric acid; and low levels of ATP confirmed activation of the fructokinase pathway. Furthermore, renal expression of inflammatory cytokines with macrophage infiltration was prominent. In contrast, diabetic fructokinase–deficient mice demonstrated significantly less proteinuria, renal dysfunction, renal injury, and inflammation. These studies identify fructokinase as a novel mediator of diabetic nephropathy and document a novel role for endogenous fructose production, or fructoneogenesis, in driving renal disease.

Changes in dengue virus (DENV) genome affect viral fitness both clinically and epidemiologically. Even in the 3' untranslated region (3' UTR), mutations could affect subgenomic flaviviral RNA (sfRNA) production and its affinity for host proteins, which are necessary for successful viral replication. Indeed, we recently showed that mutations in DENV2 3' UTR of epidemic strains increased sfRNA ability to bind host proteins and reduce interferon expression. However, whether 3' UTR differences shape the overall DENV evolution remains incompletely understood. Herein, we combined RNA phylogeny with phylogenetics to gain insights on sfRNA evolution. We found that sfRNA structures are under purifying selection and highly conserved despite sequence divergence. Only the second flaviviral nuclease-resistant RNA (fNR2) structure of DENV2 sfRNA has undergone strong positive selection. Epidemiological reports suggest that substitutions in fNR2 may drive DENV2 epidemiological fitness, possibly through sfRNA-protein interactions. Collectively, our findings indicate that 3' UTRs are important determinants of DENV fitness in human-mosquito cycles.

RNA-binding proteins (RBPs) are crucial regulators of gene expression, often composed of defined domains interspersed with flexible, intrinsically disordered regions. Determining the structure of ribonucleoprotein (RNP) complexes involving such RBPs necessitates integrative structural modeling due to their lack of a single stable state. In this study, we integrate magnetic resonance, mass spectrometry, and small-angle scattering data to determine the solution structure of the polypyrimidine-tract binding protein 1 (PTBP1/hnRNP I) bound to an RNA fragment from the internal ribosome entry site (IRES) of the encephalomyocarditis virus (EMCV). This binding, essential for enhancing the translation of viral RNA, leads to a complex structure that demonstrates RNA and protein compaction, while maintaining pronounced conformational flexibility. Acting as an RNA chaperone, PTBP1 orchestrates the IRES RNA into a few distinct conformations, exposing the RNA stems outward. This conformational diversity is likely common among RNP structures and functionally important. Our approach enables atomic-level characterization of heterogeneous RNP structures.

Since 1999, dengue outbreaks in the continental United States involving local transmission have occurred only episodically and only in Florida and Texas. In Florida, these episodes appear to be coincident with increased introductions of dengue virus into the region through human travel and migration from countries where the disease is endemic. To date, the U.S. public health response to dengue outbreaks has been largely reactive, and implementation of comprehensive arbovirus surveillance in advance of predictable transmission seasons, which would enable proactive preventative efforts, remains unsupported. The significance of our finding is that it is the first documented report of DENV4 transmission to and maintenance within a local mosquito vector population in the continental United States in the absence of a human case during two consecutive years. Our data suggest that molecular surveillance of mosquito populations in high-risk, high-tourism areas of the United States may enable proactive, targeted vector control before potential arbovirus outbreaks.