Perineuronal nets and recall of distant fear memories
PNN (green) around a parvalbumin-expressing inhibitory neuron (red) in rat V2L.
Perineuronal nets (PNN) are gauzy, carbohydrate-rich structures that envelop subsets of neurons in the central nervous system, forming a long-lived extracellular matrix that stabilizes synaptic connections between neurons. PNNs are thought to serve as physical substrates of long-term memory owing to their longevity and infrequent renewal. Elise Holter Thompson et al. (pp. 607–612) tested the role of PNNs in the retrieval of visual fear memories by training rats to respond to paired stimuli—a white light and foot shock—in an experimental setup for recall of fearful memories from the remote past. The authors report that targeted degradation of PNNs in a brain region called the lateral secondary visual cortex (V2L)—but not in the primary visual cortex—through administration of the enzyme chondroitinase disrupted the recall of distant—but not recent—visual fear memory. Synchronized oscillation of theta waves between the V2L and the basolateral amygdala, a brain region implicated in memory recall, was disrupted in chondroitinase-treated rats that displayed impaired recall of distant fear memory, suggesting disrupted information flow between the two brain regions and underscoring the role of PNNs in ensuring appropriately coordinated firing patterns during distant memory retrieval. Further, PNN degradation did not affect the formation or consolidation of visual fear memories. According to the authors, PNNs in the V2L play a crucial role in retrieving distant—but not recent—fear memories. — P.N.
Identifying inhibitors of PD-1 function
Targeting the programmed cell death-1 (PD-1) protein—a critical inhibitory receptor in T cells—with antibodies has led to promising clinical responses against cancer. However, many patients fail to respond to anti–PD-1 treatment, and the protein’s downstream signaling pathways and the molecular mechanisms by which it inhibits T cells are not well understood. Michael Peled et al. (pp. E468–E477) used the PD-1 cytoplasmic tail as a bait to affinity-purify proteins associated with PD-1 in activated T cells and used high-resolution mass spectrometry to identify these proteins. The authors identified signaling lymphocytic activation molecule-associated protein (SAP) as being indirectly associated with PD-1. The authors report that overexpressing SAP blocked the inhibitory functions of PD-1 in T cells by shielding key substrates targeted by the tyrosine phosphatase SHP2, a known mediator of PD-1 inhibition. The authors isolated T cells from patients with X-linked lymphoproliferative disease, in whom SAP is mutated and nonfunctional, and found that the T cells were hyperresponsive to PD-1 signaling. In addition, intracellular SAP levels were inversely correlated with signaling downstream of PD-1 in purified T cell subsets. The results indicate that SAP is a negative regulator of PD-1 functions and downstream signaling. Thus, SAP could serve as a potential biomarker for reduced responses to PD-1 therapy, and the findings could aid the development of therapeutic strategies against cancer, according to the authors. — S.R.
Mosaic evolution of avian skull
High-dimensional data reveals modularity in the avian skull.
Mosaic evolution refers to the observation that different functional systems can evolve traits at different rates or via different modes. Mosaic evolution is widely invoked to frame observed morphological changes, but few studies have sought to quantify the phenomenon and deduce the functional relationships that drive the underlying semiautonomous modules. Ryan N. Felice and Anjali Goswami (pp. 555–560) describe the deconstruction of mosaic evolution in the avian skull using high-dimensional morphometric data and a broad data set comprising phylogenetic samples spanning nearly all extant avian families. The authors identified seven semi-independent regions in the avian cranium that exhibit distinct rates and modes of evolution, including periods of rapid change and innovation. Further, the authors demonstrate how the different regions mirror and connect back to their disparate developmental origins. The analysis supports a longstanding hypothesis that a high degree of interaction among traits constrains diversity and evolutionary rate by restricting the direction and magnitude of response to selection pressure, according to the authors. — T.J.
Rebooting bacteriophage genomes
Bacteriophages, which are viruses that infect bacteria, have many potential applications, including controlling pathogens, medical diagnostics, and antimicrobial therapy. Tailoring phages by editing their genomes can enhance them for various applications, but phage editing is challenging, particularly for phages that target Gram-positive bacteria. Samuel Kilcher et al. (pp. 567–572) used Listeria monocytogenes L-form bacteria, which lack cell walls, to reactivate synthetic bacteriophage DNA in a process known as genome rebooting. The authors used Listeria L-form cells to reboot a variety of native Listeria phage genomes, as well as phages from other Gram-positive bacteria such as Bacillus and Staphylococcus. The L-form cells also efficiently rebooted fully synthetic in vitro-assembled phage genomes from Listeria and Bacillus phages. The authors also modified temperate phage genomes in a targeted manner to generate virulent phages and found that these engineered phages demonstrated enhanced killing efficacy. Genetically arming these synthetic phages by incorporating an additional endolysin gene as a genetic payload allowed the synthetic phages to efficiently target phage-resistant bystander cells. According to the authors, the synthetic genome rebooting strategy is a fast, efficient, and broadly applicable approach to phage engineering and could lead to the development of improved phage applications. — S.R.