Picturing molecular alterations

Two separate groups of investigators have used artificial intelligence (AI) approaches to extract information about multiple molecular alterations from histopathology cancer slides. Histopathological slides are generated from tumor biopsies as well as from surgically excised tumors, and are all-but-universally available diagnostic instruments for solid tumors. They are used by pathologists to classify tumors as benign or malignant, but more detailed information about molecular abnormalities and drivers require sequencing to date. In their experiments, researchers from the European Bioinformatics Institute (EBI), and from the University Clinic Aachen and the University of Chicago, were able to develop algorithms that could identify multiple genomic alterations, including genome duplications, specific tumor drivers and indels, across multiple solid tumor types. The Aachen group noted that “our method can be implemented on mobile hardware, potentially enabling point-of-care diagnostics for personalized cancer treatment.” More generally, the EBI group wrote, “These findings show the remarkable potential of computer vision in characterizing the molecular basis of tumor histopathology.” The papers were published back to back in the July 27, 2020, online issue of Nature Cancer.

Fishing for druggable osteoporosis targets

A study led by National University of Singapore (NUS) scientists has generated a novel transgenic fish model of osteoporosis, which was used to identify druggable osteoporosis targets and two promising new treatments. Fish bone is analogous to human bone, with similar genetic, molecular and physiological mechanisms controlling the balance between bone production and destruction, and embryos and larvae of the medaka fish (Oryzias latipes) are translucent, making it very easy to visualize changes in bone. Receptor-activator of NF-kappa β ligand (RANKL) has recently been implicated in bone homeostasis, and the authors developed a transgenic RANKL model and used it to screen for drugs that could restore homeostasis after RANKL activation. They identified two small molecules, AMG-487 and NBI-74330, that reduced osteoclast recruitment and protected against osteoporosis by blocking the activity of chemokine receptor Cxcr3.2. The paper was published in the July 27, 2020, online issue of the Proceedings of the National Academy of Sciences.

First mouse-adapted strain of SARS-CoV-2

Researchers at the Beijing Institute of Microbiology and Epidemiology and Fudan University have adapted SARS-CoV-2 to be able to infect mice. Small animal models of SARS-CoV-2 infection are among the urgently needed resources to end the pandemic. SARS-CoV-2 binds to ACE2 receptors, but it is not adapted to mouse ACE2, although there are transgenic mouse strains with human ACE2 receptors. The authors took the complementary approach, developing a viral strain that was more easily able to infect mice by serial infections of old mice. After six rounds of passaging, the resulting strain, which the team named MASCp6, was more easily able to infect both young and aged mice. The researchers sequenced the strain to reveal key mutations. The authors wrote that “this mouse-adapted strain and challenge model should be of value in evaluating vaccines and antivirals against SARS-CoV-2.” They reported their results online in Science on July 20, 2020.

Transplanted iPSCs are best of both ApoE models

By transplanting human induced pluripotent stem cells (iPSCs) with different ApoE alleles into mice, researchers at the Gladstone Institute of Neurological Disease have gained new insights into the pathological mechanism of action of ApoE4. Though ApoE variants are the strongest genetic risk variants for Alzheimer’s disease (AD), much remains to be learned about how ApoE causes disease. In their experiments, the team combined the advantages of human-specific ApoE and in vivo experimental systems and separated the effects of neuronal and microenvironmental ApoE by transplanting ApoE4 iPSCs into the brains of human ApoE3 carrier mice, and vice versa. They demonstrated that the strongest changes in gene expression patterns occurred when ApoE4 was expressed in both neurons and the microenvironment, “reaffirming the importance of incorporating the in vivo environment into experiments,” they wrote. They also showed that microglial ApoE4 contributed strongly to the microenvironmental effects of ApoE4. They reported their findings in the July 28, 2020, print issue of Cell Reports.

TXNIP inhibition nixes T2D

Scientists at the University of Alabama at Birmingham have developed a small molecule that improved multiple aspects of liver function in mouse models of diabetes by inhibiting thioredoxin-interacting protein (TXNIP). The researchers had previously identified TXNIP as a protein that was up-regulated by glucose and that was a mechanistic link between glucose toxicity and beta cell loss, suggesting that its inhibition could block the negative feedback loop of reduced insulin production, increased levels of glucose, damaged beta cells and further reduced insulin production. In their follow-up studies, they used screening and chemical optimization to develop the orally available TXNIP inhibitor SRI-37330, which “inhibited glucagon secretion and function, reduced hepatic glucose production, and reversed hepatic steatosis,” the authors wrote. They concluded that “these studies describe a newly designed chemical compound that, compared to currently available therapies, may provide a distinct and effective approach to treating diabetes.” They published their findings in the July 28, 2020, issue of Cell Metabolism.

Degradation approach targets extracellular proteins

High hopes ride on degradation as a method to therapeutically target proteins that don’t succumb to small-molecule inhibitors. The most mature version of that approach, proteolysis-targeting chimeras (PROTACS), targets intracellular proteins for degradation by the ubiquitin-proteasome system. Now, researchers at Stanford University have developed a way to target extracellular and secreted proteins to the lysosome. Collectively, membrane-bound extracellular proteins and secreted proteins make up roughly 40% of the human proteome. The Stanford group showed that their method, which they called lysosome-targeting chimeras (LYTACs), was able to target “therapeutically relevant proteins, including apolipoprotein E4, epidermal growth factor receptor, CD71 and programmed death-ligand 1. Our results establish a modular strategy for directing secreted and membrane proteins for lysosomal degradation, with broad implications for biochemical research and for therapeutics,” they wrote. Their experiments were published in the July 30, 2020, issue of Nature.

Tryptophan metabolites keep gut barrier strong

Researchers at Cornell University have identified three microbiome-produced tryptophan metabolites that improved gut barrier integrity in animal models of inflammatory bowel disease (IBD). Using both in vitro and in vivo technologies, the researchers demonstrated that indole-3-ethanol, indole-3-pyruvate and indole-3-aldehyde, all of which are the result of microbial metabolism of tryptophan, acted on the aryl hydrocarbon receptor to maintain the integrity of the gut barrier in a mouse model of colitis. “These studies provide a mechanistic understanding of how small-molecule [tryptophan] metabolites produced by the gut microbiota modulate host processes, including gut barrier function to benefit the host in diseases such as IBDs that negatively affect the intestinal epithelium,” the authors wrote. Their work appeared in the July 27, 2020, online issue of the Proceedings of the National Academy of Sciences.

Honest placebos change brain potentials

Investigators at the University of Michigan have demonstrated that placebos administered without deception changed the EEG signature of study participants engaged in an unpleasant task. Placebos can themselves reduce symptoms, which is an ongoing problem for placebo-controlled trials of some drugs, most notably antidepressants. Recent work has shown that placebos are helpful even when people know they are getting a placebo, but researchers have disagreed about whether that was due to actual changes in brain activity or reporting bias. In their experiment, the researchers exposed study participants to arousing unpleasant pictures either on their own, or after administering a placebo. They showed that when participants view such pictures after receiving a placebo and being told that placebos can still provide beneficial effects even if people know they are taking them, which, the authors wrote, “leverages one of the primary psychological mechanisms through which placebos operate: a person’s expectation that their condition will improve after receiving a treatment.” The authors showed that under those circumstances, participants who received a placebo were less likely to report emotional distress. They also showed changes in the late positive potential, an EEG signature of the process of ascribing meaning to emotions. The authors concluded that “non-deceptive placebos induce objectively measurable changes in brain state, and that prior research may have failed to observe non-deceptive placebo effects on objective biological measures because they focused on domains… that do not reliably respond to deceptive placebos induced through verbal suggestion. Put simply, if a deceptive placebo induced through verbal suggestion does not reliably impact biological outcomes in these contexts, there is no reason to expect a non-deceptive placebo should either.” They reported their results in the July 27, 2020, issue of Nature Communications.

Screening in serum yields active antibiotics

Among the many reasons for the failure of antibiotics discovery to keep up with drug resistance is that the conditions encountered by bacteria during infection are drastically different than those in laboratory media. Bacterial pathogens require a number of biological processes to cause infection that are not important to grow in laboratory media. Investigators working at McMaster University have developed a screen that specifically identified small molecules that were active in human serum. They then used their method to find antibiotics that were active against Klebsiella pneumoniae, and demonstrated that “one of these compounds, ruthenium red, was effective in a rat bloodstream infection model. Our data demonstrate that human serum is an effective tool to find new chemical matter to address the current antibiotic resistance crisis.” They reported their results in the July 21, 2020 issue of Cell Reports.

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