Seed and soil in regeneration
As far as adult regeneration goes, the lung and liver are far better than most human tissues. Even those organs, however, can become unable to repair themselves in the face of persistent injuries, such as those caused by smoking or excessive drinking. Experimentally, regenerative capacity can be restored by stem cell transplants. But frequently those transplants fail to establish themselves due to insufficient support from the microenvironment. A team from Weill Cornell Medicine has shown that the lung and liver microenvironment could be made more hospitable by inducing the expression of hepatocyte growth factor and inhibiting the expression of the protein Nox4 in the endothelial cells of the blood vessels, which are a component of the microenvironment. "Our data suggest that targeting dysfunctional perivascular and vascular cells in diseased organs can bypass fibrosis and enable reparative cell engraftment to reinstate lung and liver regeneration," the authors wrote. Their work appeared in the Aug. 30, 2017, issue of Science Translational Medicine.
Gut microbiome regulates circadian fat metabolism
The circadian transcription factor NFIL3, which regulates circadian lipid metabolism, is itself regulated by the gut microbiome. The gut microbiome is now appreciated as a contributor to human metabolism, both because gut bacteria extract energy from the human diet and promote storage of that energy as fat. Less is known, though, about how the microbiome regulates host metabolic pathway. Researchers from the University of Texas Southwestern Medical Center investigated the effects of NFIL3, which is expressed in intestinal cells, and showed that its expression there varied in a 24-hour-cycle, and that the level of expression was controlled by the composition of the gut microbiome. "These findings provide mechanistic insight into how the intestinal microbiota regulates body composition and establish NFIL3 as an essential molecular link among the microbiota, the circadian clock, and host metabolism," the authors concluded. Their work appeared in the Sept. 1, 2017, issue of Science.
Protein aggregation brings stress relief
Irreversible protein aggregation is a driving factor in many neurodegenerative disorders. But reversible protein aggregation may be a protective mechanism to shield cells in times of stress. Researchers from the Swiss ETH Zurich investigated reversible protein aggregation in yeast, and showed that the pyruvate kinase CDC19, a key metabolic enzyme and growth regulator, aggregated in glucose-deprived cells. Those aggregates were sequestered into stress granules, protecting the enzyme from degradation during stress. When starved cells were re-exposed to glucose, CDC19 disaggregated, allowing the rapid re-start of cell growth in times of plenty. The team showed that several other enzymes that play roles in cell cycle progression had the same structural features as those that allow CDC19 to reversibly aggregate, "implying that reversible aggregation represents a conserved mechanism regulating cell growth and survival," the authors wrote. They published their findings in the Aug. 28, 2017, online issue of Nature Cell Biology.
Asthma drug prevents protein aggregates
Reversible aggregation may not be all bad, but irreversible aggregation still is. Now, scientists have identified a druggable target to prevent the aggregation of alpha-synuclein, the protein that aggregates in Parkinson's diseases (PD). Much effort with respect to protein aggregation has focused on busting and/or clearing aggregates. While there have been suggestions that reducing aggregation of aggregate-prone proteins could be an alternative strategy, implementation tactics in the form of druggable regulators have been lacking for that approach. A group from Brigham and Women's Hospital developing a screen for regulators of alpha-synuclein expression, showed that agonists of the beta2-adrenoreceptor reduced alpha-synuclein levels in human cells. Epidemiological studies showed that individuals who used the brain-penetrant beta2-adrenoreceptor agonist salbutamol for treatment of their asthma had a lower risk of developing PD. The authors concluded that beta2-adrenoreceptor agonists are potential therapies for PD. Their work was published in the Sept. 1, 2017, issue of Science.
Chaperones pay more attention in glia than neurons
A team from Emory University has shown that neurons are more vulnerable to the stresses of misfolding than astrocytes, a type of glial cell, because neurons had higher levels of the protein HspBP1, which ultimately inhibited the activity of the chaperone protein Hsp70. Chaperone proteins help other proteins fold into their correct three-dimensional shapes, and for many proteins, misfolding is energetically unstable, and proteins can unfold and try to attain the correct shape multiple times with the help of chaperone proteins. The researchers compared expression and activity levels of proteins in neurons and astrocytes, and discovered that in neurons, HspBP1 inhibited CHIP, a protein that interacts with Hsp70. "Knocking down HspBP1 in neurons prevents the accumulation and aggregation of the Huntington's disease (HD) protein and ameliorates neuropathology in a HD knockin mouse model," the authors wrote. "These findings suggest that HspBP1 accounts for differential vulnerabilities of neurons and glia to misfolded proteins." They published their results in the Aug. 28, 2017, online issue of the Proceedings of the National Academy of Sciences.
Engineered bacteria shed light on chronic infections
Researchers have used bacterial engineering to create a strain of Escherichia coli that permanently expressed a reporter gene after temporary exposure to antibiotics, making it a useful tool to study the effects of antibiotic sensitivity and resistance on infections in vivo. The team showed that in contrast to bacteria that were exposed to antibiotics in vitro, a significant proportion of E. coli kept replicating in chronic in vivo infections. They also showed that nondividing bacteria did not necessarily lead to antibiotic-tolerant infections, also unlike the situation in cell culture experiments. "These results demonstrate the utility of engineered bacteria for querying pathogen behavior in vivo, and the importance of validating in vitro studies of antibiotic effects with in vivo models," the authors concluded. They published their findings in the Aug. 31, 2017, issue of Cell Host & Microbe.
Sensitive malaria biomarker could help with eradication efforts
A new biomarker for the malaria parasite Plasmodium falciparum infection is more than twice as sensitive as the most sensitive current method. For malaria eradication, it is important to be able to detect extremely low levels of P. falciparum in the blood. Researchers from the FDA looked at gene expression profiles of gametocytes, an asymptomatic stage when the overall infection level is very low, to find proteins that were expressed at that stage. They then tested their ability to detect the 25 proteins with the highest expression levels from the gametocyte stage. They found that by testing for the parasite protein Pfg17, they were able to detect infections of 10 parasites per milliliter (ml) of blood, while the Pfs25 protein detected by current tests requires 25 parasites per ml. "Cumulatively, our results suggest Pfg17 is an excellent biomarker for detecting asymptomatic infectious reservoirs otherwise missed by the most sensitive molecular method available. Our study has also improved the repertoire of transmission-stage antigens available for evaluation as candidate vaccines," the authors wrote. They published their results in the Aug. 24, 2017, online issue of the Journal of Infectious Diseases.
Novel models of pediatric solid tumors
Like adult tumors, the outlook for long-term survival decreases sharply with recurrence in children with pediatric solid tumors. Scientists at St. Jude Children's Research Hospital have developed nearly 70 orthotopic xenograft (O-PDX) models of pediatric solid tumors derived at diagnosis, recurrence and autopsy. O-PDX models are transplanted back into the organ of origin, and remain more similar to their parent tumors than subcutaneous xenografts. The team conducted basic science studies showing that "the origins of the patient-derived xenograft tumors were reflected in their gene-expression profiles and epigenomes." They also studied drug vulnerabilities and found that multiple rhabdomyosarcoma O-PDXs were sensitive to a combination of AZD-1775, irinotecan and vincristine. The authors termed their study "proof of principle for using O-PDX tumors for basic and translational research on pediatric solid tumors." They published their results in the Aug. 31, 2017, issue of Nature.
ROS extends insect life span
Reactive oxygen species (ROS) can clearly contribute to cell damage but, counterintuitively, they also have health benefits under certain circumstances, and treating patients with ROS scavengers can make things worse for cancer patients. A team from Ohio State University and the Chinese Sun Yat-Sen University showed that in insects, ROS extended life span by affecting parts of the insulin signaling pathway. That action ultimately contributed to diapause, a period of developmental rest that lengthens life span in insects. The team wrote that their results "suggest a new molecular mechanism regulating life span and help to explain the dual nature of ROS action in animals." The work appeared in the Aug. 28, 2017, online issue of the Proceedings of the National Academy of Sciences.
How neuroblastoma genes cooperate
The transcription co-factor LMO1 and amplification of the oncogene MYCN synergized in pediatric neuroblastoma to increase its aggressiveness and propensity to metastasize. Pediatric neuroblastoma is a highly aggressive cancer, and despite aggressive treatment to match, long-term survival rates for pediatric neuroblastoma patients remain below 40 percent. Researchers from the Mayo Clinic and the Dana-Farber Cancer Institute identified that synergy and investigated its potential mechanisms. They hypothesized that "LMO1 up-regulates the expression of [extracellular matrix] regulatory genes, leading, in turn, to remodeling of the extracellular matrix, assembly of focal adhesion complexes, and rearrangement of the actin cytoskeleton, which together result in enhanced invasion, motility and metastasis of cells with high levels of LMO1 expression. " When such cells also have amplified MYCN, the uncontrolled growth of such cells combines with an enhanced ability to leave the primary tumor and travel to the bloodstream, and then to distant anatomical sites. The researchers published their findings in the Aug. 31, 2017, issue of Cancer Cell.