Brain activity predicts SSRI success

Despite the fact that antidepressants are taken by more than 10% of the U.S. population, large randomized controlled trials have found little evidence that they are beneficial. However, anecdotal evidence suggests that some patients benefit strongly. Biomarkers that could predict who will benefit from current antidepressants, though, have proved elusive so far. The team focused on measuring brain activity via MRI, rather than on biological proxies for serotonergic circuit characteristics, and showed that individuals whose brains were less able to self-regulate their activity during conflict benefited more from Zoloft (sertraline) treatment. Using machine learning, the team was able to develop a model that could predict which individuals would benefit from sertraline. "We identified a medication-responsive neural phenotype within the broader clinical diagnosis of depression, which was related to the degree to which the brain could adaptively regulate emotional conflict above and beyond the brain's response to conflict itself," the authors wrote. "Leveraging brain-based measures in psychiatry will forge a path toward better treatment personalization, refined mechanistic insights and improved outcomes." They published their results in the Sept. 23, 2019, issue of Nature Human Behavior.

Anxious mitochondria shut down under stress

Researchers from the University of Helsinki and the Max-Planck Institute for Psychiatry have identified changes in mitochondrial-related gene expression that were convergent in the blood and brain tissues of stress-susceptible mice, and in panic disorder patients who were having panic attacks as part of exposure therapy. Furthermore, mice of a strain that is more resilient to stress showed the opposite gene expression changes in response to repeated stress. The authors acknowledged that "there are several caveats in comparing a post-mitotic brain region to a peripheral biospecimen, which are very different in terms of mitochondrial metabolism, but nonetheless, we observed a consistent and converging signature that warrants further investigations. Altogether, our data reinforce the utility of cross-species approaches in the identification of the biological basis of human anxiety disorders but advises careful selection of mouse strains for the best translatability of the findings." They published their findings in the Sept. 26, 2019, online issue of PLoS Genetics.

Anchoring protein is potential biomarker, target for Parkinson's disease

Investigators at Stanford University have demonstrated that the mitochondrial surface protein Miro was removed less efficiently from damaged mitochondria in fibroblasts from patients with Parkinson's disease (PD) than controls, leading to slower removal and degradation of those mitochondria. Miro anchors mitochondria to microtubules; Lrrk2 and PINK1-Parkin, three proteins implicated in familial PD, are all involved in its removal from dysfunctional mitochondria, prompting the team to take a closer look at Miro levels in PD patient samples. They showed that roughly 95% of patient samples were deficient at removing Miro. Small molecules that were able to correct the molecular defect in Miro removal also improved symptoms in both human neurons and animal models of PD. The authors predicted that their findings "will aid in guiding precision health strategies and stratifying participants for clinical trials, by first identifying patients with the Miro1 phenotype, and then testing the responses of the Miro1 marker to multiple Miro1 reducers using their own skin cells to determine personalized prognosis." Their work appeared in the Sept. 26, 2019, issue of Cell Metabolism.

Common, rare variant effects converge in schizophrenia

Nearly 150 genetic risk variants for schizophrenia have been identified via genomewide association studies (GWAS), and nearly half of those signals appear to be due to expression quantitative trait loci (eQTLs), which affect the amount of a nearby protein rather than coding for a protein themselves. Now, scientists at the Mount Sinai School of Medicine have demonstrated synergistic effects of those common variants. The team studied the effects of different combinations of risk variants in otherwise isogenic iPSC-derived cells, and showed that the effects of four separate GWAS risk loci converged in their downstream effects on neuronal gene expression patterns and synaptic structure and function. "This work identifies a synergy between SZ eQTL genes, supporting the hypothesis that common and rare SZ-associated variants occur in the same genes and/or converge on the same pathways – an unexpected finding that may apply more broadly across complex genetic disorders," the authors reported. Their work appeared in the Sept. 23, 2019, online issue of Nature Genetics.

HBA1c may need supplemental G6PD

Led by researchers from Boston University and the Broad Institute of Harvard and MIT, the Trans-Omics for Precision Medicine Program has reported that African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Levels of HbA1c, or the percentage of hemoglobin that is modified by glycosylation, is the standard way to diagnose diabetes. It is, however, an indirect measure, and HbA1c levels are also influenced by the turnover rate of red blood cells. A previous genomewide association study had demonstrated that roughly half of loci that influenced HbA1c levels affected cell turnover rather than blood glucose levels. In their current study, the team showed that variants in G6PD that were more common in African Americans and Latinx individuals lowered HbA1c levels through their effects on red blood cell turnover. They argued that "assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis." Their work appeared in the Sept. 26, 2019, online issue of the American Journal of Human Genetics.

Neurotransmitter receptor stimulates early blood cell progenitors

Researchers at Cold Spring Harbor Laboratories and Memorial Sloan-Kettering Cancer Center have identified a target to stimulate the production of red blood cells from early stage progenitor cells. There are many different causes of anemia, including by certain cancers and the chemotherapies used to treat them. Recombinant erythropoietin (EPO) can stimulate the formation of red blood cells, but it acts mainly on a late-stage progenitor, the colony-forming unit, or CFU-E. Patients who do not have enough CFU-Es because their stem cells are stalled at an earlier stage do not benefit from EPO. In their work, the authors screened for G protein-coupled receptors that would affect the formation of an earlier progenitor, the burst-forming unit (BFU-E), and identified the muscarinic acetylcholine receptor CHRM4. CHRM4 antagonists corrected anemia in mouse models of several different types of anemia, suggesting that targeting CHRM4 could be a strategy to stimulate red blood cell formation in patients that are resistant to EPO. On the scientific side, "the identification of a function of CHRM4, a receptor for neurotransmitters, in regulating BFU-E self-renewal suggests a potential connection between parasympathetic neuron activity and BFU-E self-renewal and a potential model of neural control of [blood stem cell] self-renewal." The team reported its findings in the Sept. 25, 2019, issue of Science Translational Medicine.

In seizures ER stress is best bad option

Investigators at the University of Illinois at Urbana-Champaign have demonstrated that the endoplasmic reticulum (ER) stress response protected neurons after seizures. The researchers demonstrated that after a seizure, activation of Mdm2, which added ubiquitin tags to the tumor suppressor p53, tagging it for destruction and enabling protein translation ultimately protected neurons from excitotoxicity. "Although Mdm2-p53 signaling has been shown to participate in cellular stress-induced apoptosis, our study ... demonstrates a beneficial role for ER stress response in neural excitability homeostasis after seizures. Our findings also indicate that any attempts to ameliorate seizure-induced cell death by inhibiting ER stress may actually worsen seizure severity by diminishing the homeostatic effect on neural activity induced upon ER stress," the authors wrote. "Both the positive and negative consequences of ER stress should be taken into consideration when developing and testing the next generation of seizure therapies." They reported their findings in the Sept. 26, 2019, issue of PLoS Genetics.

Antithrombin isoform protects against sepsis

Researchers at Lund University have demonstrated that the beta form of antithrombin (HbAT) provided protection in a mouse model of E. coli-induced sepsis. Sepsis is an overwhelming inflammatory response that is most often set off by infections. The inflammatory program is coordinated by the transcription factor NF-kappaB. The team showed that HbAT bound to three receptors – CD13, CD300f and LRP-1 – that all play a role in blocking the proinflammatory activity of NF-kappaB. "The role of these receptors in severe infectious diseases has not been intensively studied, making them promising drug targets," the authors wrote. "In a lethal E. coli infection model, survival rates increased when mice were treated with HbAT" – but not the more common alpha form of antithrombin – "one hour and five hours after infection. The treatment also resulted in a reduction of the inflammatory response and less severe organ damage." The team published its results in the Sept. 23, 2019, online issue of Nature Microbiology.

Designer cytokine shows promise for diabetes, muscle atrophy

Researchers at Monash University have created a chimeric cytokine that had multiple positive effects on health and metabolism in obese mice. Ciliary neurotrophic factor (CNTF) and IL-6 are two cytokines that have positive effects on metabolism, but both are problematic in terms of clinical use, as IL-6 is pro-inflammatory and CNTF can provoke an antibody response. In their work, the team combined aspects of both cytokines, and fused them to the Fc domain of immunoglobulin G. The resulting protein did not provoke an antibody response, nor was it pro-inflammatory. Treatment with the chimeric protein, which the investigators named IC7Fc, improved metabolic function and prevented fatty liver in mice. IC7Fc also prevented muscle atrophy. The researchers concluded that IC7Fc "is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic." They reported their findings Sept. 26, 2019, in Nature.

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