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Erratum [Erratum]
(Source: FASEB Journal)
Source: FASEB Journal - January 2, 2018 Category: Biology Tags: Erratum Source Type: research

Telomere length dynamics in early life: the blood-and-muscle model [Research]
We examined a blood-and-muscle model during early life, focusing on TL trajectories in leukocytes, representing the highly proliferative hematopoietic system, and skeletal muscle, a minimally proliferative tissue. Leukocyte TL (LTL) and skeletal muscle TL (MTL) were measured in 28 fetuses and 73 children. LTL and MTL were highly variable across individuals (sd: fetal LTL = 0.72 kb, MTL = 0.72 kb; children LTL = 0.81 kb, MTL = 0.82 kb) but were highly correlated within individuals (fetuses, r = 0.76, P
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Sabharwal, S., Verhulst, S., Guirguis, G., Kark, J. D., Labat, C., Roche, N. E., Martimucci, K., Patel, K., Heller, D. S., Kimura, M., Chuang, D., Chuang, A., Benetos, A., Aviv, A. Tags: Research Source Type: research

Increased miR-124-3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowth via their transfer into neurons [Research]
Neuronal inflammation is the characteristic pathologic change of acute neurologic impairment and chronic traumatic encephalopathy after traumatic brain injury (TBI). Inhibiting the excessive inflammatory response is essential for improving the neurologic outcome. To clarify the regulatory mechanism of microglial exosomes on neuronal inflammation in TBI, we focused on studying the impact of microglial exosomal miRNAs on injured neurons in this research. We used a repetitive (r)TBI mouse model and harvested the injured brain extracts from the acute to the chronic phase of TBI to treat cultured BV2 microglia in vitro. The mic...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Huang, S., Ge, X., Yu, J., Han, Z., Yin, Z., Li, Y., Chen, F., Wang, H., Zhang, J., Lei, P. Tags: Research Source Type: research

SIRT1 antagonizes liver fibrosis by blocking hepatic stellate cell activation in mice [Research]
Hepatic stellate cells (HSCs) are a major source of fibrogenesis in the liver, contributing to cirrhosis. When activated, HSCs transdifferentiate into myofibroblasts and undergo profound functional alterations paralleling an overhaul of the transcriptome, the mechanism of which remains largely undefined. We investigated the involvement of the class III deacetylase sirtuin [silent information regulator 1 (SIRT1)] in HSC activation and liver fibrosis. SIRT1 levels were down-regulated in the livers in mouse models of liver fibrosis, in patients with cirrhosis, and in activated HSCs as opposed to quiescent HSCs. SIRT1 activati...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Li, M., Hong, W., Hao, C., Li, L., Wu, D., Shen, A., Lu, J., Zheng, Y., Li, P., Xu, Y. Tags: Research Source Type: research

{alpha}-Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway [Research]
Skeletal muscle atrophy due to excessive protein degradation is the main cause for muscle dysfunction, fatigue, and weakening of athletic ability. Endurance exercise is effective to attenuate muscle atrophy, but the underlying mechanism has not been fully investigated. α-Ketoglutarate (AKG) is a key intermediate of tricarboxylic acid cycle, which is generated during endurance exercise. Here, we demonstrated that AKG effectively attenuated corticosterone-induced protein degradation and rescued the muscle atrophy and dysfunction in a Duchenne muscular dystrophy mouse model. Interestingly, AKG also inhibited the express...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Cai, X., Yuan, Y., Liao, Z., Xing, K., Zhu, C., Xu, Y., Yu, L., Wang, L., Wang, S., Zhu, X., Gao, P., Zhang, Y., Jiang, Q., Xu, P., Shu, G. Tags: Research Source Type: research

Endogenous glucocorticoid signaling in chondrocytes attenuates joint inflammation and damage [Research]
Previous studies demonstrated that endogenous glucocorticoid signaling in osteoblasts promotes inflammation in murine immune arthritis. The current study determined whether disruption of endogenous glucocorticoid signaling in chondrocytes also modulates the course and severity of arthritis. Tamoxifen-inducible chondrocyte-targeted glucocorticoid receptor-knockout (chGRKO) mice were generated by breeding GRflox/flox mice with tamoxifen-inducible collagen 2a1 Cre (Col2a1-CreERT2) mice. Antigen-induced arthritis (AIA) and K/BxN serum transfer–induced arthritis (STIA) were induced in both chGRKO mice and their Cre-negati...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Tu, J., Stoner, S., Fromm, P. D., Wang, T., Chen, D., Tuckermann, J., Cooper, M. S., Seibel, M. J., Zhou, H. Tags: Research Source Type: research

Positional stable isotope tracer analysis reveals carbon routes during ammonia metabolism of Aedes aegypti mosquitoes [Research]
In this study, we used low- and high-resolution liquid chromatography-mass spectrometry (LC/MS) techniques to investigate the role of glucose during ammonia detoxification. Mosquitoes were fed a blood meal supplemented with [1,2-13C2]glucose, and downstream metabolites were measured for 24 h. Quantification of [13C] amino acids in the entire mosquito body was conducted without sample derivatization using selected reaction monitoring of mass transitions that are indicative of the structural position of [13C] atom incorporation. Identification of unlabeled and [13C] isotopologs of 43 compounds, including amino acids, amino a...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Horvath, T. D., Dagan, S., Lorenzi, P. L., Hawke, D. H., Scaraffia, P. Y. Tags: Research Source Type: research

Identification of truncated form of NosP as a transcription factor to regulate the biosynthesis of nosiheptide [Research]
Nosiheptide (NOS), a typical member of the thiopeptides, possesses strong activities against multidrug-resistant, gram-positive bacterial pathogens. Similar to other thiopeptides, the biosynthetic pathway of NOS belongs to a ribosomally synthesized and posttranslationally modified peptide system. Bioinformatics analysis of the NOS gene cluster suggests that nosP gene encodes a homologous protein of the Streptomyces antibiotic regulatory protein (SARP) family. In the present study, the actual initiation codon of nosP was identified by comparison of potential initiation codons GUG and AUG. In contrast to previous predictions...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Wu, X., Jin, L., Zhang, H., Tong, R., Ma, M., Chen, Y. Tags: Research Source Type: research

Carbonic anhydrase III protects osteocytes from oxidative stress [Research]
Osteocytes are master orchestrators of bone remodeling; they control osteoblast and osteoclast activities both directly via cell-to-cell communication and indirectly via secreted factors, and they are the main postnatal source of sclerostin and RANKL (receptor activator of NF-kB ligand), two regulators of osteoblast and osteoclast function. Despite progress in understanding osteocyte biology and function, much remains to be elucidated. Recently developed osteocytic cell lines—together with new genome editing tools—has allowed a closer look at the biology and molecular makeup of these cells. By using single-cell...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Shi, C., Uda, Y., Dedic, C., Azab, E., Sun, N., Hussein, A. I., Petty, C. A., Fulzele, K., Mitterberger-Vogt, M. C., Zwerschke, W., Pereira, R., Wang, K., Pajevic, P. D. Tags: Research Source Type: research

EVI and MDS/EVI are required for adult intestinal stem cell formation during postembryonic vertebrate development [Research]
The gene ectopic viral integration site 1 (EVI) and its variant myelodysplastic syndrome 1 (MDS)/EVI encode zinc-finger proteins that have been recognized as important oncogenes in various types of cancer. In contrast to the established role of EVI and MDS/EVI in cancer development, their potential function during vertebrate postembryonic development, especially in organ-specific adult stem cells, is unclear. Amphibian metamorphosis is strikingly similar to postembryonic development around birth in mammals, with both processes taking place when plasma thyroid hormone (T3) levels are high. Using the T3-dependent metamorphos...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Okada, M., Shi, Y.-B. Tags: Research Source Type: research

Exploiting mitochondrial and oxidative vulnerabilities with a synthetic analog of pancratistatin in combination with piperlongumine for cancer therapy [Research]
Harsh adverse effects as a result of nonspecific targeting of chemotherapeutics currently pose obstacles in cancer therapy; thus, it would be invaluable to devise novel approaches to specifically target cancer cells. The natural compound pancratistatin (PST) has been shown to preferentially induce apoptosis in a variety of cancer cell types. Recently, several analogs of PST were shown to be efficacious in inducing apoptosis in a variety of aggressive cancer cell types via cancer cell mitochondrial targeting; it caused dissipation of mitochondrial membrane potential and decreased oxygen consumption, and with isolated mitoch...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Ma, D., Gilbert, T., Pignanelli, C., Tarade, D., Noel, M., Mansour, F., Gupta, M., Ma, S., Ropat, J., Curran, C., Vshyvenko, S., Hudlicky, T., Pandey, S. Tags: Research Source Type: research

Selective inhibitory effects of zinc on cell proliferation in esophageal squamous cell carcinoma through Orai1 [Research]
Zinc, an essential micronutrient, has a cancer preventive role. Zinc deficiency has been shown to contribute to the progression of esophageal cancer. Orai1, a store-operated Ca2+ entry (SOCE) channel, was previously reported to be highly expressed in tumor tissues removed from patients with esophageal squamous cell carcinoma (ESCC) with poor prognosis, and elevation of its expression contributes to both hyperactive intracellular Ca2+ oscillations and fast cell proliferation in human ESCC cells. However, the molecular basis of cancer preventive functions of zinc and its association with Orai1-mediated cell proliferation rem...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Choi, S., Cui, C., Luo, Y., Kim, S.-H., Ko, J.-K., Huo, X., Ma, J., Fu, L.-W., Souza, R. F., Korichneva, I., Pan, Z. Tags: Research Source Type: research

Tet1 overexpression leads to anxiety-like behavior and enhanced fear memories via the activation of calcium-dependent cascade through Egr1 expression in mice [Research]
Ten-eleven translocation methylcytosine dioxygenase 1 (Tet1) initiates DNA demethylation by converting 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) at CpG-rich regions of genes, which have key roles in adult neurogenesis and memory. In addition, the overexpression of Tet1 with 5-hmC alteration in patients with psychosis has also been reported, for instance in schizophrenia and bipolar disorders. The mechanism underlying Tet1 overexpression in the brain; however, is still elusive. In the present study, we found that Tet1-transgenic (Tet1-TG) mice displayed abnormal behaviors involving elevated anxiety and enha...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Kwon, W., Kim, H.-S., Jeong, J., Sung, Y., Choi, M., Park, S., Lee, J., Jang, S., Kim, S. H., Lee, S., Kim, M. O., Ryoo, Z. Y. Tags: Research Source Type: research

lncRNA AK017368 promotes proliferation and suppresses differentiation of myoblasts in skeletal muscle development by attenuating the function of miR-30c [Research]
Long noncoding RNAs (lncRNAs) have been reported to play diverse roles in biologic and pathologic processes, including myogenesis. We found that lncRNA AK017368 is highly expressed in skeletal muscle cells. Functional analyses showed that overexpression of AK017368 promoted proliferation and restrained differentiation of myoblasts; whereas inhibition of AK017368 had completely opposite effects in vitro. In mice, knockdown of AK017368 promoted muscle hypertrophy in vivo. RNA molecules of AK017368 acted mechanistically as competing endogenous RNAs to target micro-RNA (miR)-30c, which was supported by the results of bioinform...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Liang, T., Zhou, B., Shi, L., Wang, H., Chu, Q., Xu, F., Li, Y., Chen, R., Shen, C., Schinckel, A. P. Tags: Research Source Type: research

Eliciting improved antibacterial efficacy of host proteins in the presence of antibiotics [Research]
We recently reported the aptitude of a membrane-active lipopeptide (C10OOc12O) to sensitize gram-negative bacilli (GNB) to host antibacterial proteins. Here we explored the potential of harnessing such capacity in the presence of antibiotics. For this purpose, we compared Escherichia coli sensitization to antibiotics in broth and plasma; assessed inner and outer membrane damages using scanning electron microscopy, dyes, and mutant strains; and assessed the ability to affect disease course using the mouse peritonitis–sepsis model for mono- and combination therapies. We found that by altering permeability of both outer...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Jammal, J., Zaknoon, F., Mor, A. Tags: Research Source Type: research

Effects of aging and resistance training in rat tendon remodeling [Research]
In elderly persons, weak tendons contribute to functional limitations, injuries, and disability, but resistance training can attenuate this age-related decline. We evaluated the effects of resistance training on the extracellular matrix (ECM) of the calcaneal tendon (CT) in young and old rats and its effect on tendon remodeling. Wistar rats aged 3 mo (young, n = 30) and 20 mo (old, n = 30) were divided into 4 groups: young sedentary, young trained, old sedentary (OS), and old trained (OT). The training sessions were conducted over a 12-wk period. Aging in sedentary rats showed down-regulation in key genes that regulated EC...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Marqueti, R. C., Durigan, J. L. Q., Oliveira, A. J. S., Mekaro, M. S., Guzzoni, V., Aro, A. A., Pimentel, E. R., Selistre-de-Araujo, H. S. Tags: Research Source Type: research

BaP exposure causes oocyte meiotic arrest and fertilization failure to weaken female fertility [Research]
Benzo[a]pyrene (BaP) is a ubiquitous environmental pollutant and carcinogen that is frequently found in particulate matter, with a diameter of ≤2.5 μm (PM2.5). It has been reported to interrupt the normal reproductive system, but the exact molecular basis has not been clearly defined. To understand the underlying mechanisms regarding how BaP exposure disrupts female fertility, we evaluated oocyte quality by assessing the critical regulators and events during oocyte meiotic maturation and fertilization. We found that BaP exposure compromised the mouse oocyte meiotic progression by disrupting normal spindle assembly, c...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Zhang, M., Miao, Y., Chen, Q., Cai, M., Dong, W., Dai, X., Lu, Y., Zhou, C., Cui, Z., Xiong, B. Tags: Research Source Type: research

GTRAP3-18 regulates food intake and body weight by interacting with pro-opiomelanocortin [Research]
Pro-opiomelanocortin (POMC)-expressing neurons provide α-melanocyte–stimulating hormone (α-MSH), which stimulates melanocortin 4 receptor to induce hypophagia by AMPK inhibition in the hypothalamus. α-MSH is produced by POMC cleavage in secretory granules and released. However, it is not known yet whether any posttranscriptional regulatory mechanism of POMC signaling exists upstream of the secretory granules in neurons. Here we show that glutamate transporter–associated protein 3-18 (GTRAP3-18), an anchor protein that retains interacting proteins in the endoplasmic reticulum, is a critical reg...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Aoyama, K., Bhadhprasit, W., Watabe, M., Wang, F., Matsumura, N., Nakaki, T. Tags: Research Source Type: research

PI3K{gamma} ablation does not promote diabetes in db/db mice, but improves insulin sensitivity and reduces pancreatic {beta}-cell apoptosis [Research]
PI3K has emerged as a promising target for the treatment of obesity and insulin resistance; however, previous studies have indicated that PI3K activity in pancreatic β cells is required for normal insulin secretion in response to glucose. Hence, a possible deterioration of insulin secretion capacity in patients who are predisposed to the failure of pancreatic β-cell function is a major concern for the pharmacologic inhibition of PI3K. To address this issue, we investigated the effects of PI3K ablation in db/db diabetic mice, a genetic model of obesity-driven β-cell failure and diabetes. Mice that lacked PI3K...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Breasson, L., Sardi, C., Becattini, B., Zani, F., Solinas, G. Tags: Research Source Type: research

{alpha}-Linolenic acid-derived metabolites from gut lactic acid bacteria induce differentiation of anti-inflammatory M2 macrophages through G protein-coupled receptor 40 [Research]
In this study, we examined the effect of ALA and its gut lactic acid bacteria metabolites 13-hydroxy-9(Z),15(Z)-octadecadienoic acid (13-OH) and 13-oxo-9(Z),15(Z)-octadecadienoic acid (13-oxo) on the differentiation of M2 macrophages from bone marrow–derived cells (BMDCs) and investigated the underlying mechanisms. BMDCs were stimulated with ALA, 13-OH, or 13-oxo in the presence of IL-4 or IL-13 for 24 h, and significant increases in M2 macrophage markers CD206 and Arginase-1 (Arg1) were observed. In addition, M2 macrophage phenotypes were less prevalent following cotreatment with GPCR40 antagonists or inhibitors of ...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Ohue-Kitano, R., Yasuoka, Y., Goto, T., Kitamura, N., Park, S.-B., Kishino, S., Kimura, I., Kasubuchi, M., Takahashi, H., Li, Y., Yeh, Y.-S., Jheng, H.-F., Iwase, M., Tanaka, M., Masuda, S., Inoue, T., Yamakage, H., Kusakabe, T., Tani, F., Shimatsu, A., T Tags: Research Source Type: research

FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing [Research]
Free fatty acid receptors 2 and 3 (FFAR2/FFA2/GPR43 and FFAR3/FFA3/GPR41) are mammalian receptors for gut microbiota–derived short-chain fatty acids (SCFAs). These receptors are promising drug targets for obesity, colitis, colon cancer, asthma, and arthritis. Here, we demonstrate that FFAR2 and FFAR3 interact to form a heteromer in primary human monocytes and macrophages via proximity ligation assay, and during heterologous expression in HEK293 cells via bimolecular fluorescence complementation and fluorescence resonance energy transfer. The FFAR2-FFAR3 heteromer displayed enhanced cytosolic Ca2+ signaling (1.5-fold ...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Ang, Z., Xiong, D., Wu, M., Ding, J. L. Tags: Research Source Type: research

Endothelial cells promote triple-negative breast cancer cell metastasis via PAI-1 and CCL5 signaling [Research]
Endothelial cells (ECs) in the tumor microenvironment have been reported to play a more active role in solid tumor growth and metastatic dissemination than simply providing the physical structure to form conduits for blood flow; however, the involvement of ECs in the process of triple-negative breast cancer (TNBC) metastasis has not been addressed. Here, we demonstrate that ECs—when mixed with TNBC cells—could increase TNBC cell metastatic potency. After treatment with TGF-β to induce endothelial–mesenchymal transition (EMT), TNBC cells could produce plasminogen activator inhibitor-1 (PAI-1) and stim...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Zhang, W., Xu, J., Fang, H., Tang, L., Chen, W., Sun, Q., Zhang, Q., Yang, F., Sun, Z., Cao, L., Wang, Y., Guan, X. Tags: Research Source Type: research

Pronounced energy restriction with elevated protein intake results in no change in proteolysis and reductions in skeletal muscle protein synthesis that are mitigated by resistance exercise [Research]
Preservation of lean body mass (LBM) may be important during dietary energy restriction (ER) and requires equal rates of muscle protein synthesis (MPS) and muscle protein breakdown (MPB). Currently, the relative contribution of MPS and MPB to the loss of LBM during ER in humans is unknown. We aimed to determine the impact of dietary protein intake and resistance exercise on MPS and MPB during a controlled short-term energy deficit. Adult men (body mass index, 28.6 ± 0.6 kg/m2; age 22 ± 1 yr) underwent 10 d of 40%-reduced energy intake while performing unilateral resistance exercise and consuming lower protein...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Hector, A. J., McGlory, C., Damas, F., Mazara, N., Baker, S. K., Phillips, S. M. Tags: Research Source Type: research

Myeloid receptor CD36 is required for early phagocytosis of myocardial infarcts and induction of Nr4a1-dependent mechanisms of cardiac repair [Research]
Phagocytosis after myocardial infarction (MI) is a prerequisite to cardiac repair. Recruited monocytes clear necrotic cardiomyocytes and differentiate into cardiac macrophages. Some studies have linked apoptotic cell receptors on cardiac macrophages to tissue repair; however, the contribution of precursor monocyte phagocytic receptors, which are the first to interact with the cardiac parenchyma, is unclear. The scavenger receptor cluster of differentiation (CD)36 protein was detected on cardiac Ly6cHI monocytes, and bone marrow–derived Cd36 was essential for both early phagocytosis of dying cardiomyocytes and for sma...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Dehn, S., Thorp, E. B. Tags: Research Source Type: research

Presenilin1/{gamma}-secretase protects neurons from glucose deprivation-induced death by regulating miR-212 and PEA15 [Research]
Reduced cerebral glucose utilization is found in aged individuals and often is an early sign of neurodegeneration. Here, we show that under glucose deprivation (GD) conditions, decreased expression of presenilin 1 (PS1) results in decreased neuronal survival, whereas increased PS1 increases neuronal survival. Inhibition of -secretase also decreases neuronal survival under GD conditions, which suggests the PS1/-secretase system protects neurons from GD-induced death. We also show that neuronal levels of the survival protein, phosphoprotein enriched in astrocytes at ~15 kDa (PEA15), and its mRNA are regulated by PS1/-secreta...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Huang, Q., Voloudakis, G., Ren, Y., Yoon, Y., Zhang, E., Kajiwara, Y., Shao, Z., Xuan, Z., Lebedev, D., Georgakopoulos, A., Robakis, N. K. Tags: Research Source Type: research

The deubiquitinating enzyme USP48 stabilizes TRAF2 and reduces E-cadherin-mediated adherens junctions [Research]
The tumor necrosis factor receptor–associated factor 2 (TRAF2) is a second messenger adaptor protein that plays an essential role in propagating TNF-α-mediated signaling pathways. Modulation of TRAF2 activity by ubiquitination is well studied; however, the deubiquitinating enzyme (DUB), which regulates TRAF2 stability, has not been identified. Here we reveal USP48 as the first identified DUB to deubiquitinate and stabilize TRAF2 in epithelial cells. Down-regulation of USP48 increases K48-linked polyubiquitination of TRAF2 and reduces TRAF2 protein levels. Interestingly, USP48 only targets the TRAF2 related to J...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Li, S., Wang, D., Zhao, J., Weathington, N. M., Shang, D., Zhao, Y. Tags: Research Source Type: research

Organ- and cell-specific immune responses are associated with the outcomes of intracerebral hemorrhage [Research]
Severe brain injury significantly influences immune responses; however, the levels at which this influence occurs and which neurogenic pathways are involved are not well defined. Here, we used MRI to measure spleen volume and tissue diffusion changes in patients with intracerebral hemorrhage (ICH). We observed increased capillary exchange and spleen shrinkage by d 3 post-ICH, with recovery by d 14. The extent of spleen shrinkage was associated with brain hematoma size, and a reduced progression of perihematomal edema was observed in the presence of severe spleen shrinkage. At the cellular level, lymphopenia was present in ...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Zhang, J., Shi, K., Li, Z., Li, M., Han, Y., Wang, L., Zhang, Z., Yu, C., Zhang, F., Song, L., Dong, J.-F., La Cava, A., Sheth, K. N., Shi, F.-D. Tags: Research Source Type: research

Proline-dependent and basophilic kinases phosphorylate human TRPC6 at serine 14 to control channel activity through increased membrane expression [Research]
In this study, an unbiased phosphoproteomic screen of human TRPC6 identified several novel serine phosphorylation sites. The phosphorylation site at serine 14 of TRPC6 is embedded in a basophilic kinase motif that is highly conserved across species. We confirmed serine 14 as a target of MAPKs and proline-directed kinases like cyclin-dependent kinase 5 (Cdk5) in cell-based as well as in vitro kinase assays and quantitative phosphoproteomic analysis of TRPC6. Phosphorylation of TRPC6 at serine 14 enhances channel conductance by boosting membrane expression of TRPC6, whereas protein stability and multimerization of TRPC6 are ...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Hagmann, H., Mangold, N., Rinschen, M. M., Koenig, T., Kunzelmann, K., Schermer, B., Benzing, T., Brinkkoetter, P. T. Tags: Research Source Type: research

Dyslipidemia impairs mitochondrial trafficking and function in sensory neurons [Research]
Mitochondrial trafficking plays a central role in dorsal root ganglion (DRG) neuronal cell survival and neurotransmission by transporting mitochondria from the neuronal cell body throughout the bundles of DRG axons. In type 2 diabetes (T2DM), dyslipidemia and hyperglycemia damage DRG neurons and induce mitochondrial dysfunction; however, the impact of free fatty acids and glucose on mitochondrial trafficking in DRG neurons remains unknown. To evaluate the impact of free fatty acids compared to hyperglycemia on mitochondrial transport, primary adult mouse DRG neuron cultures were treated with physiologic concentrations of p...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Rumora, A. E., Lentz, S. I., Hinder, L. M., Jackson, S. W., Valesano, A., Levinson, G. E., Feldman, E. L. Tags: Research Source Type: research

Identification of a new adtrp1-tfpi regulatory axis for the specification of primitive myelopoiesis and definitive hematopoiesis [Research]
A genomic variant in the human ADTRP [androgen-dependent tissue factor (TF) pathway inhibitor (TFPI) regulating protein] gene increases the risk of coronary artery disease, the leading cause of death worldwide. TFPI is the TF pathway inhibitor that is involved in coagulation. Here, we report that adtrp and tfpi form a regulatory axis that specifies primitive myelopoiesis and definitive hematopoiesis, but not primitive erythropoiesis or vasculogenesis. In zebrafish, there are 2 paralogues for adtrp (i.e., adtrp1 and adtrp2). Knockdown of adtrp1 expression inhibits the specification of hemangioblasts, as shown by decreased e...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Wang, L., Wang, X., Wang, L., Yousaf, M., Li, J., Zuo, M., Yang, Z., Gou, D., Bao, B., Li, L., Xiang, N., Jia, H., Xu, C., Chen, Q., Wang, Q. K. Tags: Research Source Type: research

Real-time acquisition of transendothelial electrical resistance in an all-human, in vitro, 3-dimensional, blood-brain barrier model exemplifies tight-junction integrity [Research]
The blood–brain barrier (BBB) consists of endothelial cells, astrocytes, and pericytes embedded in basal lamina (BL). Most in vitro models use nonhuman, monolayer cultures for therapeutic-delivery studies, relying on transendothelial electrical resistance (TEER) measurements without other tight-junction (TJ) formation parameters. We aimed to develop reliable, reproducible, in vitro 3-dimensional (3D) models incorporating relevant human, in vivo cell types and BL proteins. The 3D BBB models were constructed with human brain endothelial cells, human astrocytes, and human brain pericytes in mono-, co-, and tricultures. ...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Maherally, Z., Fillmore, H. L., Tan, S. L., Tan, S. F., Jassam, S. A., Quack, F. I., Hatherell, K. E., Pilkington, G. J. Tags: Research Source Type: research

Protease-activated receptor 2 activates airway apical membrane chloride permeability and increases ciliary beating [Research]
In this study, we examined the protease-activated receptor (PAR)-2, a GPCR previously shown to regulate airway cell cytokine and mucus secretion, and transepithelial Cl– current. PAR-2 is activated by proteases secreted by airway neutrophils and pathogens. We cultured various airway cell lines, primary human and mouse sinonasal cells, and human bronchial cells at air–liquid interface and examined them using molecular biology, biochemistry, and live-cell imaging. We found that PAR-2 is expressed basolaterally, where it stimulates both intracellular Ca2+ release and Ca2+ influx, which activates low-level nitric o...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: McMahon, D. B., Workman, A. D., Kohanski, M. A., Carey, R. M., Freund, J. R., Hariri, B. M., Chen, B., Doghramji, L. J., Adappa, N. D., Palmer, J. N., Kennedy, D. W., Lee, R. J. Tags: Research Source Type: research

Cathepsin B-mediated CD18 shedding regulates leukocyte recruitment from angiogenic vessels [Research]
Cathepsin B (CtsB) contributes to atherosclerosis and cancer progression by processing the extracellular matrix and promoting angiogenesis. Although CtsB was reported to promote and reduce angiogenesis, there is no mechanistic explanation that reconciles this apparent discrepancy. CtsB cleaves CD18 from the surface of immune cells, but its contribution to angiogenesis has not been studied. We developed an in vivo technique for visualization of immune cell transmigration from corneal vessels toward implanted cytokines. Wild-type (WT) leukocytes extravasated from limbal vessels, angiogenic stalks, and growing tip vessels and...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Nakao, S., Zandi, S., Sun, D., Hafezi-Moghadam, A. Tags: Research Source Type: research

A novel role for ceramide synthase 6 in mouse and human alcoholic steatosis [Research]
We examined the effects of pharmacologic ceramide synthesis inhibition on hepatic PLIN2 expression, steatosis, and glucose and lipid homeostasis in mice with alcoholic steatosis and in ethanol-incubated human hepatoma VL17A cells. In cells, pharmacologic inhibition of ceramide synthase reduced lipid accumulation by reducing PLIN2 RNA stability. The subtype ceramide synthase (CerS)6 was specifically up-regulated in experimental alcoholic steatosis in vivo and in vitro and was up-regulated in zone 3 hepatocytes in human alcoholic steatosis. In vivo ceramide reduction by inhibition of de novo ceramide synthesis reduced PLIN2 ...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Williams, B., Correnti, J., Oranu, A., Lin, A., Scott, V., Annoh, M., Beck, J., Furth, E., Mitchell, V., Senkal, C. E., Obeid, L., Carr, R. M. Tags: Research Source Type: research

Experimental confirmation of the C3 tickover hypothesis by studies with an Ab (S77) that inhibits tickover in whole serum [Research]
The complement component 3 (C3) tickover hypothesis was put forward in the early 1970s to account for the spontaneous activation of the alternative complement pathway that occurs after the genetic absence or in vitro depletion of Factor I, the enzyme that is essential for the breakdown of C3b. The hypothesis was widely accepted, but experimental demonstration of the tickover was elusive. A phage Ab against C3b that inhibited the alternative complement pathway, but not the classical pathway, was described in 2009. Studies using this Ab in a variety of assays have now demonstrated that it acts primarily by inhibiting tickove...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Lachmann, P. J., Lay, E., Seilly, D. J. Tags: Research Source Type: research

In vitro and in vivo imaging and tracking of intestinal organoids from human induced pluripotent stem cells [Research]
Human intestinal organoids (hIOs) derived from human pluripotent stem cells (hPSCs) have immense potential as a source of intestines. Therefore, an efficient system is needed for visualizing the stage of intestinal differentiation and further identifying hIOs derived from hPSCs. Here, 2 fluorescent biosensors were developed based on human induced pluripotent stem cell (hiPSC) lines that stably expressed fluorescent reporters driven by intestine-specific gene promoters Krüppel-like factor 5 monomeric Cherry (KLF5mCherry) and intestine-specific homeobox enhanced green fluorescence protein (ISXeGFP). Then hIOs were efficien...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Jung, K. B., Lee, H., Son, Y. S., Lee, J. H., Cho, H.-S., Lee, M.-O., Oh, J.-H., Lee, J., Kim, S., Jung, C.-R., Kim, J., Son, M.-Y. Tags: Research Source Type: research

Exosomes in postshock mesenteric lymph are key mediators of acute lung injury triggering the macrophage activation via Toll-like receptor 4 [Research]
Acute lung injury (ALI) is a common cause of morbidity in patients after severe injury due to dysregulated inflammation, which is believed to be driven by gut-derived inflammatory mediators carried via mesenteric lymph (ML). We have previously demonstrated that nano-sized extracellular vesicles, called exosomes, secreted into ML after trauma/hemorrhagic shock (T/HS) have the potential to activate immune cells in vitro. Here, we assess the function of ML exosomes in the development of T/HS-induced ALI and the role of TLR4 in the ML exosome–mediated inflammatory response. ML exosomes isolated from rats subjected to T/H...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Kojima, M., Gimenes-Junior, J. A., Chan, T. W., Eliceiri, B. P., Baird, A., Costantini, T. W., Coimbra, R. Tags: Research Source Type: research

Normoxic cells remotely regulate the acid-base balance of cells at the hypoxic core of connexin-coupled tumor growths [Research]
ATP fuels the removal of metabolic end-products, including H+ ions that profoundly modulate biological activities. Energetic resources in hypoxic tumor regions are constrained by low-yielding glycolysis, and any means of reducing the cost of acid extrusion, without compromising pH homeostasis, would therefore be advantageous for cancer cells. Some cancers express connexin channels that allow solute exchange between cells, and we propose that, via this route, normoxic cells supply hypoxic neighbors with acid-neutralizing HCO3– ions. This hypothesis was tested by imaging cytoplasmic pH in spheroidal tissue growths of c...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Dovmark, T. H., Hulikova, A., Niederer, S. A., Vaughan-Jones, R. D., Swietach, P. Tags: Research Source Type: research

Switching of the substrate specificity of protein tyrosine phosphatase N12 by cyclin-dependent kinase 2 phosphorylation orchestrating 2 oncogenic pathways [Research]
The protein tyrosine phosphatase nonreceptor type 12 (PTPN12) is a multifunctional protein and has elicited much research attention because its decreased protein level has been associated with poor prognosis of several types of cancers. Recently, we have solved the crystal structure of the phosphatase domain of PTPN12, which disclosed a specific PTPN12–insert–loop harboring a cyclin-dependent kinase 2 (CDK2) phosphorylation site. However, the functional significance of this phosphorylation is undefined. In the present study, we found that S19 site phosphorylation of PTPN12 by CDK2 discharged its antitumor activ...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Li, H., Yang, D., Ning, S., Xu, Y., Yang, F., Yin, R., Feng, T., Han, S., Guo, L., Zhang, P., Qu, W., Guo, R., Song, C., Xiao, P., Zhou, C., Xu, Z., Sun, J.-P., Yu, X. Tags: Research Source Type: research

Testicular cells exhibit similar molecular responses to cigarette smoke condensate ex vivo and in vivo [Research]
Male exposure to cigarette smoke is associated with seminal defects and with congenital anomalies and childhood cancers in offspring. In mice, paternal exposure to cigarette smoke condensate (CSC) causes molecular defects in germ cells and phenotypic effects in their offspring. Here we used an ex vivo testicular explant model and in vivo exposure to determine the concentration at which CSC impairs spermatogenesis and offspring development. We explanted testis tissue at postnatal day (P)5.5 and cultured it until P11.5. Assessment of growth parameters by analyzing expression of cell-specific markers revealed that the explant...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Esakky, P., Hansen, D. A., Drury, A. M., Felder, P., Cusumano, A., Moley, K. H. Tags: Research Source Type: research

Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation-induced osteoporosis [Research]
Bone atrophy and its related fragility fractures are frequent, late side effects of radiotherapy in cancer survivors and have a detrimental impact on their quality of life. In another study, we showed that parathyroid hormone 1-34 and anti-sclerostin antibody attenuates radiation-induced bone damage by accelerating DNA repair in osteoblasts. DNA damage responses are partially regulated by the ubiquitin proteasome pathway. In the current study, we examined whether proteasome inhibitors have similar bone-protective effects against radiation damage. MG132 treatment greatly reduced radiation-induced apoptosis in cultured osteo...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Chandra, A., Wang, L., Young, T., Zhong, L., Tseng, W.-J., Levine, M. A., Cengel, K., Liu, X. S., Zhang, Y., Pignolo, R. J., Qin, L. Tags: Research Source Type: research

Defective lysosomal clearance of autophagosomes and its clinical implications in nonalcoholic steatohepatitis [Research]
Autophagic impairment is implicated in nonalcoholic fatty liver disease (NAFLD), but the molecular mechanism is unclear. We found that autophagic flux was significantly inhibited in 3 murine models of NAFLD. Interestingly, the number of acidic organelles and the level of mature cathepsin D were reduced, suggesting defective lysosome acidification. Asparagine synthetase (ASNS) was induced by endoplasmic reticulum stress, leading to the generation of asparagine, which inhibited lysosome acidification. Both steatotic- and asparagine-treated hepatocytes showed reduced lysosomal acidity and retention of lysosomal calcium. Knock...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Wang, X., Zhang, X., Chu, E. S. H., Chen, X., Kang, W., Wu, F., To, K.-F., Wong, V. W. S., Chan, H. L. Y., Chan, M. T. V., Sung, J. J. Y., Wu, W. K. K., Yu, J. Tags: Research Source Type: research

Formyl-peptide receptor 2 governs leukocyte influx in local Staphylococcus aureus infections [Research]
Leukocytes express formyl-peptide receptors (FPRs), which sense microbe-associated molecular pattern (MAMP) molecules, leading to leukocyte chemotaxis and activation. We recently demonstrated that phenol-soluble modulin (PSM) peptides from highly pathogenic Staphylococcus aureus are efficient ligands for the human FPR2. How PSM detection by FPR2 impacts on the course of S. aureus infections has remained unknown. We characterized the specificity of mouse FPR2 (mFpr2) using a receptor-transfected cell line, homeobox b8 (Hoxb8), and primary neutrophils isolated from wild-type (WT) or mFpr2–/– mice. The influx of l...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Weiss, E., Hanzelmann, D., Fehlhaber, B., Klos, A., von Loewenich, F. D., Liese, J., Peschel, A., Kretschmer, D. Tags: Research Source Type: research

PLA2 and ENPP6 may act in concert to generate phosphocholine from the matrix vesicle membrane during skeletal mineralization [Hypothesis]
Mineralization is a key process in the formation of bone and cartilage in vertebrates, involving the deposition of calcium- and phosphate-containing hydroxyapatite (HA) mineral within a collagenous matrix. Inorganic phosphate (Pi) accumulation within matrix vesicles (MVs) is a fundamental stage in the precipitation of HA, with PHOSPHO1 being identified as the principal enzyme acting to produce Pi. PHOSPHO1 is a dual-specific phosphocholine/phosphoethanolamine phosphatase enriched in mineralizing cells and within MVs. However, the source and mechanism by which PHOSPHO1 substrates are formed before mineralization have not be...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Stewart, A. J., Leong, D. T. K., Farquharson, C. Tags: Hypothesis Source Type: research

De novo digenic mutations of telomere-associated proteins and inflammasomes initiate many chronic human diseases: a hypothesis [Hypothesis]
Many age-related human diseases have inflammatory components of uncertain causes. It has been proposed that some may be initiated or sustained by doubly mutated immune cells that have both inappropriately activated inflammasomes and enhanced replicative potential. Genes of cells that express mutant TERT and NLRP3 proteins are presumed to be at increased risk for mutagenesis because they reside in subtelomeric regions of chromatin that are deficient in DNA repair mechanisms. Expanded clones of proinflammatory cells can occur throughout one’s lifetime and could represent an alternative explanation for some forms of pat...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Marchesi, V. T. Tags: Hypothesis Source Type: research

Application and utility of mass cytometry in vaccine development [Review]
Mass cytometry enables highly multiplexed profiling of cellular immune responses in limited-volume samples, advancing prospects of a new era of systems immunology. The capabilities of mass cytometry offer expanded potential for deciphering immune responses to infectious diseases and to vaccines. Several studies have used mass cytometry to profile protective immune responses, both postinfection and postvaccination, although no vaccine-development program has yet systematically employed the technology from the outset to inform both candidate design and clinical evaluation. In this article, we review published mass cytometry ...
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Reeves, P. M., Sluder, A. E., Paul, S. R., Scholzen, A., Kashiwagi, S., Poznansky, M. C. Tags: Review Source Type: research

A Crack At CRISPR: A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution by Jennifer A. Doudna and Samuel H. Sternberg Houghton Mifflin Harcourt, Boston, 2017 [Book Review]
(Source: FASEB Journal)
Source: FASEB Journal - January 2, 2018 Category: Biology Authors: Haselkorn, R. Tags: Book Review Source Type: research

The Fortunate Intersection of Schizophrenia and the Pill [Editorial]
(Source: FASEB Journal)
Source: FASEB Journal - January 2, 2018 Category: Biology Tags: Editorial Source Type: research

Erratum [Errata]
(Source: FASEB Journal)
Source: FASEB Journal - November 30, 2017 Category: Biology Tags: Errata Source Type: research