Solid organ transplantation from hepatitis C virus–positive (HCV-positive) deceased donors into HCV-negative recipients is a recent approach aimed to expand the donor organ pool in the setting of severe shortage. Good short-term outcomes have been reported with this approach in combination with direct-acting antivirals. In this issue of the JCI, Zahid and colleagues have characterized early viral kinetics and the genetic landscape of donor-to-recipient HCV transmission using single-genome sequencing. In seven HCV-negative recipients of four HCV-positive donor organs, productive infection with a highly diverse viral population was seen by day three after transplantation. The degree of genetic diversity seen in recipients of HCV-positive organs was unlike the narrow genetic bottleneck typically observed with acute HCV acquisition from intravenous drug use or sexual activity. All recipients achieved HCV cure with treatment. The consequences of acute infection with a genetically diverse HCV population are unknown; however, early clinical experience with this transplantation strategy is promising.
Christine M. Durand, Michael A. Chattergoon
Lactation is a unique period in which the maternal skeleton acts as a storehouse to provide substantial calcium to milk. Women who exclusively breastfeed lose an average of 210 mg of calcium per day, which doubles or triples with twins and triplets. Data from rodent and clinical studies are consistent with skeletal calcium being released to provide much of the calcium needed for milk production. This is programmed to occur independently of dietary calcium intake or intestinal calcium absorption, which remains at the prepregnant rate in breastfeeding women. After weaning, the skeleton is restored to its prior mineralization and strength, but the factors that regulate this remain to be elucidated.
Brittany A. Ryan, Christopher S. Kovacs
Multiple myeloma (MM) is a relatively common hematologic malignancy, and up to half of patients with MM present with renal dysfunction at the time of diagnosis. MM-associated renal injury has been linked to an excess level of monoclonal immunoglobulin free light chains (FLCs) in the circulation; however, it is not clear how these FLCs drive renal pathology. In this issue of the JCI, Ying et al. unravel a novel mechanism by which FLCs mediate renal injury in MM by inducing fibrotic and inflammatory pathways in the kidney. Specifically, FLC-mediated production of H2O2 was shown to activate JAK2/STAT1 signaling, increase production of IL-1β via induction of capsase-1, and promote activation of TGF-β via αvβ6 integrin. Moreover, the authors identified a tryptophan residue within a specific monoclonal FLC that was required for optimal H2O2 production and downstream signaling. A better understanding of the drivers of MM-associated renal injury has potential for the identification of promising therapeutic targets.
Erin B. Taylor, Michael J. Ryan
In this issue of the JCI, Panigrahy et al. demonstrate that preoperative administration of the antiinflammatory drug ketorolac or specialized proresolving mediators (SPM) called resolvins increases disease-free survival rates and prevents metastasis after surgery and chemotherapy in mouse models of cancer. The antitumor response was partially mediated by tumor-specific T cell immunity and immunological memory.
Esra Güç, Jeffrey W. Pollard
Motile cilia provide propulsion, and immotile ones are enriched with receptors. Both are required to establish left-right identity in the developing embryo and are also implicated in a wide range of human diseases. Abnormalities in cilial function underlie heterotaxy congenital heart disease (CHD) occurring in individuals with laterality disturbance. Mitochondrial function and cellular energetics, through mTOR and autophagy, are now linked with cilial function, revealing new mechanisms and candidate genes for syndromic human disease. In the current issue of the JCI, Burkhalter et al. ask the question: Can mitochondrial disturbances produce ciliopathy and does this explain some cases of heterotaxy?
Bill Chaudhry, Deborah J. Henderson
Autophagy is a Greek-derived concept that means “self-eating” and is increasingly recognized as an important regulator of homeostasis and disease. In this issue of the JCI, Yeganeh et al. report the important finding that intrinsic autophagy is required for normal progression of lung development. Conditional deletion of the beclin 1–encoding gene (Becn1) specifically within lung epithelial cells of embryonic mice resulted in neonatal lethal respiratory distress that was associated with negative impacts on airway branching and differentiation of airway epithelial cell lineages. The authors draw speculative parallels with the alveolar simplification phenotype of bronchopulmonary dysplasia in premature human infants and suggest that stimulation of autophagy by cAMP-dependent kinase activation might conceivably rescue these phenotypes.
David Warburton, Saverio Bellusci
Anemia is defined by low levels of circulating hemoglobin, resulting in insufficient tissue oxygenation. This condition results from both genetic and nutritional factors and affects more than a billion people worldwide. For the inherited anemias, progress made over the last 40 years has increased our understanding of the structural basis for normal red cell membrane function and allowed definition of the genetic and pathophysiological bases of many human RBC membrane disorders. Despite these advances, there are continued uncertainties in the genotype-phenotype relationship in cases of severe, membrane-linked anemia. In this issue of the JCI, Gallagher and colleagues have identified a severe form of inherited anemia that results from aberrant splicing of α-spectrin, which in turn leads to abnormal erythrocyte membrane structure and function. The identification and characterization of this splicing-associated genetic disease will facilitate diagnosis and treatment of severe anemia in affected patients. These findings not only improve understanding of red cell disorders, they are likely to impact many disciplines, as the disease-associated alternate branch point utilization defined in the report may be the underlying etiology for many other inherited or acquired disorders.
As the opioid addiction crisis reaches epidemic levels, the identification of opioid analgesics that lack abuse potential may provide a path to safer treatment of chronic pain. Preclinical studies have demonstrated that galanin affects physical dependence and rewarding actions associated with morphine. In the brain and periphery, galanin and opioids signal through their respective GPCRs, GalR1–3 and the μ-opioid receptor (MOR). In this issue of the JCI, Cai and collaborators reveal that heteromers between GalR1 and MOR in the rat ventral tegmental area attenuate the potency of methadone, but not other opioids, in stimulating the dopamine release that produces euphoria. These studies help us understand why some synthetic opioids, such as methadone, do not trigger the release of dopamine in the mesolimbic system but still possess strong analgesic properties.
Randal A. Serafini, Venetia Zachariou
In this issue of the JCI, Capitano et al. demonstrate that the secreted form of the DNA-binding chromatin factor DEK regulates hematopoiesis. It is known that DEK can be secreted by macrophages and other cells, but no function has been attached to secreted DEK. Capitano et al. showed that extracellular DEK activates signaling through the CXCL2 receptor, which in turn enhances the proliferation of hematopoietic stem cells and decreases hematopoietic progenitor cell numbers both in vivo and in vitro. These results offer the opportunity to expand transplantable stem cells to improve outcomes in patients undergoing bone marrow transplant.
David M. Bodine
Growing evidence implicates altered mTORC1 signaling cascades in the pathophysiology of depression, suggesting that direct modulation of mTORC1 signaling may offer novel therapeutic potential. In this issue of the JCI, Kato and colleagues reported that administration of NV-5138, a recently developed synthetic leucine analog, has a rapid and sustained antidepressant action in rat models via activation of mTORC1 signaling. The investigators also found that the antidepressant effect of NV-5138 is mediated by upregulation of brain-derived neurotrophic factor (BDNF) signaling and that NV-5138 treatment produces rapid synaptic responses in the medial prefrontal cortex. These findings highlight the direct activation of mTORC1 signaling as a potential pharmacological intervention for the treatment of depression.
Yuto Hasegawa, Xiaolei Zhu, Atsushi Kamiya
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