How failing hearts try to save themselves

Researchers at the University of Iowa have identified a protein fragment of the structural protein junctophilin-2 that could partially prevent pathological processes contributing to heart failure. In the normally functioning heart, junctophilin-2 is important for excitation-contraction (E-C) coupling, the translation of electrical excitement into heartbeats. In their work, the team showed that junctophilin-2 was cleaved during cardiac stress, which "liberates an N-terminal fragment (JP2NT) that translocates to the nucleus, binds to genomic DNA and controls expression of a spectrum of genes in cardiomyocytes." In mice with experimentally induced heart failure, overexpression of that fragment could ameliorate the progression of heart failure, while its loss accelerated heart failure. "These data reveal a self-protective mechanism in failing cardiomyocytes that transduce mechanical information (E-C uncoupling) into salutary transcriptional reprogramming in the stressed heart," the authors wrote. Their work appeared in the Nov. 9, 2018, issue of Science.

Psoriasis and plaques

Scientists at Washington University in St. Louis have identified the mechanism by which the skin autoimmune condition psoriasis raised the risk for cardiovascular disease. In addition to their primary issue, some autoimmune diseases, including psoriasis, rheumatoid arthritis and lupus, raise the risk for cardiovascular disease. In their experiments, the team showed that T cells in psoriasis skin plaques were stimulated by interleukin-17 (IL-17), in the plaques to home to the arteries, and mediated collagen-induced changes to the extracellular matrix there that entrapped HDL and LDL cholesterol. Depleting helper T cells, neutralizing IL-17 or inhibiting the enzyme that is responsible for the cross-linking of collagen could all interrupt that process. The team concluded that "interleukin-17 can reduce lipoprotein trafficking and increase vascular stiffness by, at least in part, remodeling collagen." They published their work in the Nov. 8, 2018, issue of Cell Metabolism.

Synthetic lethal target for sarcomas discovered

The chromatin remodeling complex SWI/SNF, which controls gene transcription through interactions with chromatin, is mutated in roughly 20 percent of all cancers. SWI/SNF is made up of multiple proteins, and depending on which proteins participate in a given assembly, there are three distinct SWI/SNF complexes. Researchers from the Dana-Farber Cancer Institute have identified one of those complexes, ncBAF, as a synthetic lethal target for specific sarcomas. In their work, the team showed that ncBAF interacted with the zinc finger transcription factor CTCF, and that tumors driven by mutations in another SWI/SNF complex, cBAF, were dependent on ncBAF for their survival. The work identified several therapeutic targeting opportunities that could be used to exploit the synthetic lethal relationship between the two SWI/SNF complexes. More generally, it highlighted "the importance of understanding subunit-specific contributions to complex assembly and function when designing strategies to target [SWI/SNF]-perturbed cancers," the authors wrote. Their findings appeared in the Nov. 5, 2018, online issue of Nature Cell Biology.

Onc: Orphan noncoding, oncology

Scientists at the University of California at San Francisco have identified a novel small noncoding RNA that drove breast cancer metastasis in animal models. Several types of noncoding RNAs have previously been identified as molecules that contribute to tumor cell growth, and the team systematically screened blood samples from breast cancer patients to identify other such small noncoding RNAs. They identified T3p, which is an RNA component of the telomerase gene, as a small noncoding RNA that increased the expression of prometastatic genes. The team also showed that T3p was a component of tumor cell-derived exosomes, suggesting that it could have a role in metastasis of cells that are not producing it themselves. The authors noted that beyond the specifics of the role of T3p in breast cancer metastasis, "the approaches and concepts presented here are generalizable and can be applied to other cancer types. Taken together, our findings raise the possibility that further examination of the cancer-specific RNA landscape may yield novel strategies in developing diagnostic and therapeutic methods in breast cancer." Their work appeared in the Nov. 5, 2018, online issue of Nature Medicine.

How resistant bacteria lock in their gains

Researchers from Boston University have gained new insights into how bacteria move from transient antibiotic resistance based on the expression of drug efflux pumps to permanent resistance due to mutations. The researchers investigated whether the overexpression of drug efflux pumps, which protect bacteria against a multitude of antibiotics while they are expressed, can also provide a window of opportunity enabling them to mutate. The authors looked at expression levels of the efflux pump AcrAB and showed that at the single cell level, higher AcrAB levels were correlated with lower levels of the DNA repair enzyme mutS. "Understanding the initial evolutionary trajectory of resistant strains may suggest strategies for treating infections, such as combination therapies involving antibiotics and efflux pump inhibitors," the authors wrote. Their work appeared in the Nov. 9, 2018, online issue of Science.

Efflux pumps protect against more than antibiotics

A team at Dartmouth College has shown that in a chronic infection, multidrug efflux pumps could protect the fungus Candida lusitaniae from antifungal bacterial and host factors as well as from antifungal drugs, which could explain how drug-resistant infections can arise in treatment-naïve patients. In their work, the team conducted repeated deep sequencing of the transcription factor MRR-1, which controls the expression of the multidrug efflux pump MDR-1. They showed that there was a high level of MRR-1 allele diversity within a single sample from a cystic fibrosis patient with a chronic polymicrobial lung infection typical of such patients. They showed that such samples contained low levels of fungi with MRR-1 variants capable of inducing resistance to the standard antifungal fluconazole. "We provide evidence that these drug-resistant fungi may arise indirectly in response to other factors present in the infection," the authors wrote. Furthermore, though levels of drug-resistant strains were too low to be detected with current standard methods, "alternative methods may be able to identify drug-resistant subpopulations and thus positively impact patient care." The team reported its results in the Nov. 2, 2018, online issue of the Proceedings of the National Academy of Sciences.

Template-free Cas9 for accurate editing

Researchers from the Massachusetts Institute of Technology and Harvard University have used machine learning to identify Cas9 enzymes that could precisely edit base pairs without a need for a template. Such template-free editing is typically imprecise, and so it has been assumed that template-free editing is useful only for disrupting gene function, not for precise repair. In their experiments, the authors showed some guide RNAs are able to induce the desired repair in at least half of all instances even without a template DNA, so-called precise-50 editing. The team "experimentally confirmed precise-50 insertions and deletions in 195 human disease-relevant alleles, including correction in primary patient-derived fibroblasts of pathogenic alleles to wild-type genotype for Hermansky–Pudlak syndrome and Menkes disease," the authors wrote. That experimental confirmation "establishes an approach for precise, template-free genome editing." Their work appeared in the Nov. 8, 2018, issue of Nature.

Blocking complement protects synapses in AD

Aggregates of misfolded tau protein, which are toxic to synapses, are a major feature of late-stage Alzheimer's disease (AD), as well as other neurodegenerative disorders collectively known as the tauopathies. Researchers from Roche Holding AG subsidiary Genentech Inc. have searched for changes in synapses that occurred after the accumulation of tau had begun, but before synaptic damage was obvious. They showed that a critical intermediate between tau and synaptic damage was innate immune complement protein C1q, and that antibodies to C1q could protect animals from synaptic destruction in mouse models of familial AD. The authors concluded that "inhibiting complement-mediated synapse removal by microglia could be a potential therapeutic target for Tau-associated neurodegeneration." Their work appeared in the Nov. 1, 2018, online issue of Cell.

Critical protein for intracellular antigen recognition found

Scientists at Washington University in St. Louis have developed a method to screen for key proteins that permit dendritic cells to present antigens to T cells, and used it to identify the protein Wdfy-4 as critical for antigen presentation of both viral and tumor immunogens. Mice lacking the gene for Wdfy-4 were unable to fend off viral infections as well as immunogenic tumors that can normally be controlled by T cells. Their antigen-presenting cells developed normally, however, enabling the team to establish a new model system for studying antigen presentation of intracellular pathogens and the mutated proteins that allow the immune system to recognize tumor cells. In a commentary that accompanied the paper, authors from Cornell University wrote that the model system could be used to better understand how to strengthen the presentation of intracellular nonself antigens, which in turn would "inform effective vaccine design for cancer and also for infectious diseases such as tuberculosis, Ebola, malaria, and AIDS." Paper and commentary appeared in the Nov. 8, 2018, issue of Science.

AWOL cGAS is novel DNA repair player

Researchers at the Chinese Tongji University School of Medicine have identified Cyclic GMP–AMP synthase (cGAS) as an enzyme that suppressed DNA repair in the nucleus. Normally found in the cytosol, cGAS is a DNA sensor that activates innate immunity. After DNA damage, cGAS moves to the nucleus, but its role there had been unclear. In their experiments, the team showed that cGAS interacted with the DNA repair enzyme poly-(ADP-ribose) polymerase (PARP-1), impeding PARP-1's ability to repair DNA. In both cell culture and xenograft animal models, knocking down cGAS inhibited tumor growth. The team concluded that "nuclear cGAS suppresses homologous-recombination-mediated repair and promotes tumor growth, and that cGAS therefore represents a potential target for cancer prevention and therapy." They reported their results in the Oct. 24, 2018, issue of Nature.