Xu Etal Research Articles

Toward a Universal Solution: Editing Compatibility into Pluripotent Stem Cells.

In this issue of Cell Stem Cell, Xu etal. (2019) demonstrate that editing iPSCs' major histocompatibility antigens may potentially provide a small set of universally compatible stem cell lines for therapies. However, these modifications may result in patient minor histocompatibility responses and deficiencies in their Tcell response repertoire to infection and cancer.

DIPping into the Fly Visual System

The nervous system relies on a combinatorial code of protein interactions that determine wiring specificity. Two complementary studies by Cosmanescu etal. (2018) and Xu etal. (2018) present the most comprehensive biophysical and structural analysis of the cell-recognition proteins DIP and Dpr to date, and the discovery of key functions of DIP-α and Dpr6/10 in the wiring of the Drosophila visual system.

Tuning Apoptosis and Neuroinflammation: TBK1 Restrains RIPK1

Partial loss of TANK-binding kinase 1 (TBK1) causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Xu etal. identify the role of TBK1 in suppressing neuroinflammation and apoptosis by its inhibition of the receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and elucidate how aging and genetic susceptibility together cause neuroinflammation.

Hitting HIV’s Harpoon

The HIV-1 fusion peptide is a target for broadly neutralizing antibodies. In a recent issue of Nature Medicine, Xu etal. (2018) provide proof-of-concept that vaccination with fusion peptide followed by vaccination with an envelope glycoprotein trimer can induce antibodies in animal models that neutralize diverse HIV-1 viruses.

A Mechanosensitive GPCR that Detects the Bloody Force

Mechanoreceptors mediate a wide variety of physiological processes, such as hearing, touch, proprioception, and blood flow regulation. It is generally believed that mechanoreceptors are force-gated ion channels. Now, Xu etal. uncover a GPCR that is activated by shear force in endothelial cells of blood vessels.

TFIID and MYB Share a Therapeutic Handshake in AML

Selectively disrupting oncogenic transcription factors in cancer remains an elusive ambition of targeted therapeutics. In this issue of Cancer Cell, Xu etal. provide an elegant proof-of-concept study demonstrating that interaction between MYB and the general transcriptional coactivator TFIID can be specifically disrupted to mediate a therapeutic effect in AML.

The Burgeoning World of Immunometabolites: Th17 Cells Take Center Stage

Dysregulation of the Th17/Treg balance is a key driver of autoimmunity. A new study by Xu etal. (2017) has revealed that small-molecule inhibition of 2-hydroxyglutarate synthesis skews Th17 differentiation to the Treg lineage, which is protective against autoimmune inflammation.

Illuminating the Neuronal Architecture Underlying Context in Fear Memory

Context plays a foundational role in determining how to interpret potentially fear-producing stimuli, yet the precise neurobiological substrates of context are poorly understood. In this issue of Cell, Xu etal. elegantly show that parallel neuronal circuits are necessary for two distinct roles of context in fear conditioning.

Time to Think About Nutrient Needs in Chronic Disease

There is renewed interest in health benefits of folic acid supplementation since the China Stroke Prevention Primary Prevention Trial (CSPPT) showed the potential benefits of folic acid inpreventing stroke in Chinese adults with hypertension.1 It has long been known that folic acid prevents neural tube defects, which are among the most severe anddebilitating congenital birth defectsworldwide. The CSPPTwas terminated earlywhen800μgof folic acid in combination with 10 mg of enalapril significantly reduced primarystroke incidencecomparedwith theenalapril alone treatment arm. This finding was unexpected as other studies had failed to find a preventive effect of folic acid supplementation on cardiovascular events.2 In this issue of JAMA Internal Medicine, Xu et al3 report findings from a prespecified CSPPT substudy that demonstrated that the folic acid–enalapril combination was more effective than enalapril alone in the secondary prevention of renal function decline among Chinese adults with hypertension across a spectrum of mild to moderate chronic kidney disease (CKD). Folic acid is commonly administered to treat hyperhomocysteinemia, but thebenefits ofhomocysteine loweringon the prevention or management of most chronic diseases associatedwith hyperhomocysteinemia remains unproven.2 In the renal substudy of the CSPPT,3 Xu and colleagues report that 42% of participants with CKD exhibited hyperhomocysteinemia (serum homocysteine ≥15 μM) and 24% had diabetes, comparedwithonly26%withhyperhomocysteinemiaand12% with diabetes in those without CKD. Individuals who were homozygous for theMTHFR C677T polymorphism, a genetic variant that expresses anenzymewith reduced5-methyltetrahydrofolate synthesis activity, exhibited the greatest reduction inserumhomocysteine followingfolicacid–enalapril treatmentbecause theirbaseline levelsof circulatinghomocysteine werehigher. This finding is consistentwith other studies suggesting that the current recommended dietary intake for folatemaynotbeadequate for individualshomozygous for the MTHFR 677T variantwhen homocysteine lowering is used as the functional biomarker to assess folate status.4 Importantly, the folicacid–enalapril combinationwasmore effective in reducing rates of renal dysfunction in individuals with CKD (odds ratio [OR], 0.44; 95% CI, 0.26-0.75) compared with enalapril treatment alone, with the primary outcome measure being a prespecified level of decline in the estimated glomerular filtration rate (eGFR).3 The folic acid– enalapril treatment significantly reduced other measures of renal dysfunction in addition to the 21% reduction in risk for theprimaryoutcomecomparedwith theenalapril-onlygroup. These included secondary outcome measures of rapid decline in renal function (OR,0.67;95%CI,0.47-0.96) andacomposite eventmeasure (OR,0.62;95%CI,0.43-0.90); bothwere significantly reduced in the group receiving the folic acid– enalapril combination compared with the enalapril group. Therewasnoevidence forprimarypreventionofCKD ineither arm of the study. Hyperhomocystenemia is a common finding in patients with CKD. However, folic acid–induced reductions in serum homocysteine levels did not affect kidney function in other studies.5,6Xuet al hypothesized that thesedifferencesmaybe owing to the inclusion of other B vitamins, including vitamin B12, in previous vitamin supplementation trials on renal function.Also, the level of folic acid supplementationvariedmarkedly among these trials. The study by Xu et al administered folic acid at levels below 1 mg/d, whereas other studies administered folic acid at much higher levels. Dose may be an importantmodifier of efficacy and toxic effects, especially for specific clinical populations.Forexample, inpatientswithdiabetic nephropathy, subjects receiving 2.5 mg/d folic acid, 25mg/d vitamin B6, and 1mg/d vitamin B12 exhibited greater decreases in serumhomocysteine thandid those receivingplacebo, but kidney function (measured by eGFR) unexpectedly decreased more in the treatment group than in the placebo group.5 In a related study, patients with advanced kidney or end-stage renal diseaseswere treatedwith40mg/d folic acid, 100mg/d vitaminB6, and 2mg/d vitaminB12 daily. Therewas no effect of treatment on all-cause mortality, stroke, or amputation of lower extremities compared with placebo.6 Folic acid is a synthetic, provitamin formof folate that is processed tonatural folate by the enzymedihydrofolate reductase. Very high intakes of folic acid may result in saturation of dihydrofolate reductase activity. Folic acid binds tightly to the folate receptor (FRα), aglycoprotein that is anchored to thecellmembrane of epithelial cells. It is possible that because FRα is expressed in the kidney, the kidneymaybemoreharmedbyunmetabolized folic acid, especially in subjects with kidney disease or impaired kidney function, as observed in a population with diabetic nephropathy.5 Folic acid–induced nephrotoxic effects has been demonstrated in mouse models.7 AnothermajordifferenceamongtheCKDtrialswas theuse of enalapril in the studydesign byXuet al.3 The results of this studydemonstrated that enalapril interactswith folate in human physiology, as enalapril treatment alone in the absence of supplemental folic acid increased serumfolateby5.1 ng/mL (to convert ng/mL to nmol/L,multiply by 2.266), with amodest decrease in serum homocysteine (0.2 μM). While the mechanisms for this interaction are unknown and should be explored, this drug-nutrient interactionmayunderlie the secondary prevention of renal function decline observed in this study. Dietary reference intakes are established to give guidance foradequate intake levelsofessentialnutrients forhealthy individuals, but there is increasing awareness that these recommendations may not apply to populations with chronic Related article page 1443 Effects of Folate on Chronic Kidney Disease Progression Original Investigation Research

A Death Trap for Microglia

Microglia, immune cells of the brain, originate from erythromyeloid precursors, far from the central nervous system. Xu etal. (2016) in this issue of Developmental Cell and Casano etal. (2016) recently in Cell Reports show that apoptotic neurons act as bait to "trap" microglia into colonizing the developing brain.

Resemble and Inhibit: When RLR Meets TGF-β

In this issue, Xu etal. (2014) show that innate antiviral RIG-I-like receptors (RLR) signaling represses TGF-β-induced growth inhibition, epithelial-mesenchyme transition (EMT), and regulatory Tcell (Treg) differentiation via IRF3-mediated Smads function.

Assembling Cell Ensembles

The way the hippocampus processes information and encodes memories in the form of "cell assemblies" is likely determined in part by how its circuits are wired up during development. In this issue, Xu etal. now provide new insight into how neurons arising from a single common precursor migrate to their final destination and form functionally synchronous ensembles.

On the Bahadur representation of sample quantiles for widely orthant dependent sequences

It can be found that widely orthant dependent (WOD) random variables are weaker than extended negatively orthant dependent (END) random variables, while END random variables are weaker than negatively orthant dependent (NOD) and negatively associated (NA) random variables. In this paper, we investigate the Bahadur representation of sample quantiles based on WOD sequences. Our results extend the corresponding ones of Ling [N.X. Ling, The Bahadur representation for sample quantiles under negatively associated sequence, Statistics and Probability Letters 78(16) (2008), 2660-2663], Xu et al. [S.F. Xu, L. Ge, Y. Miao, On the Bahadur representation of sample quantiles and order statistics for NA sequences, Journal of the Korean Statistical Society 42(1) (2013), 1-7] and Li et al. [X.Q. Li, W.Z. Yang, S.H. Hu, X.J. Wang, The Bahadur representation for sample quantile under NOD sequence, Journal of Nonparametric Statistics 23(1) (2011), 59-65] for the case of NA sequences or NOD sequences.

Protein arginine methylation in hepatic glucose metabolism regulation: Histone or nonhistone? That is the question

As Xu etal. stated,1 the previous study by Krones-Herzig etal. clearly demonstrated the functional significance of protein arginine methyltransferase-4 [PRMT4; also known as coactivator-associated arginine methyltransferase-1 (CARM-1)]-dependent regulation of hepatic glucose production in cultured hepatocytes.2 Specifically, they showed that PRMT4 was recruited to the cyclic adenosine monophosphate (cAMP) response element of promoters of both phosphoenol pyruvate carboxykinase (PEPCK) and glucose 6-phosphatase catalytic subunit (G6Pase), which resulted in the increased methylation of arginine 17 on histone H3 and acetylation of histone H4. These results indicated that cAMP response element-binding protein (CREB) might recruit PRMT4 and other known histone acetyltransferases, such as CREB-binding protein (CBP)/p300, onto the promoters of gluconeogenic genes. Indeed, phosphorylation of serine 133 of CREB by cAMP-dependent protein kinase is a key mechanism for the recruitment of CBP/p300 and subsequent activation of CREB-target gene transcription.3 Although we showed that protein arginine methyltransferase-1 (PRMT1) is critical in activating FoxO1-dependent gluconeogenesis by promoting arginine methylation of FoxO1,4 we failed to detect any PRMT1-dependent increase in arginine methylation of histone H3 or H4, at least using the adenovirus-mediated overexpression system in hepatocytes (data not shown). Indeed, we suspect that FoxO1-dependent transcriptional activation might be quite a bit more complicated, because CBP/p300, a potent histone acetyltransferase that normally activates transcription factors, was shown to be involved in the direct acetylation/inhibition of FoxO1.5 Furthermore, recent studies also indicated that histone deacetylase 3 was recruited onto the FoxO1-binding sites of both PEPCK and G6Pase in primary hepatocytes,6 suggesting that certain regions of gluconeogenic promoters might be potentially hypoacetylated. Currently, we are in the process of generating liver-specific knockout mice for PRMT1 to directly address this issue. Further studies utilizing this mouse model will be helpful to decipher the complex histone codes in the regulation of hepatic gluconeogenic gene expression. Dahee Choi B.S.*, Kyoung-Jin Oh Ph.D.*, Seung-Hoi Koo Ph.D.*, * Division of Biochemistry and Molecular Biology, Department of Molecular Cell Biology and Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.

LUMENating Blood Vessels

The acquisition of a lumen is an essential step in vascular morphogenesis. In this issue of Developmental Cell, Xu etal. (2011) show that the small GTPase Rasip is a critical regulator of cytoskeleton dynamics and cell adhesion, which together drive the emergence of vascular lumens.

Swine Flu Neutralized

![Figure][1] CREDIT: XU ET AL. The 2009 H1N1 flu virus had an unusually low infection rate in elderly people. An antibody isolated from survivors of the 1918 flu pandemic was recently shown to cross-neutralize 2009 H1N1 viruses. Xu et al. (p. [357][2], published online 25 March) report

Variation in dynamics of phytochrome A inArabidopsisecotypes and mutants

ABSTRACTPhytochromes are photoreceptors in plants which can exist in two different conformations: the red light‐absorbing form (Pr) and the far‐red light‐absorbing form (Pfr), depending on the light quality. The Pfrform is the physiologically active conformation. To attenuate the Pfrsignal for phytochrome A (phyA), at least two different mechanisms exist: destruction of the molecule and dark reversion. Destruction is an active process leading to the degradation of Pfr. Dark reversion is the light‐independent conversion of physiologically active Pfrinto inactive Pr. Here, we show that dark reversion is not only an intrinsic property of the phytochrome molecule but is modulated by cellular components. Furthermore, we demonstrate that dark reversion of phyA may be observed inArabidopsisecotype RLD but not in otherArabidopsisecotypes. For the first time, we have identified mutants with altered dark reversion and destruction in a set of previously isolated loss of function PHYA alleles (Xuet al. Plant Cell1995, 7, 1433–1443). Therefore, the dynamics of the phytochrome molecule itself need to be considered during the characterization of signal transduction mutants.