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1.  Addendum 2: Forum for Injection Technique, India 
The second addendum to the Forum for Injection Techniques (FIT), India recommendations, first published in 2012 and followed by an addendum in 2013, covers various important issues. It describes how the impact of the so-called non-modifiable factors, which influence the injection technique, can be modulated; provides fresh information on timing of glucagon-like peptide 1 receptor agonist injections, methods of minimizing pain during injections, amyloidosis, and factors that impact adherence to insulin therapy. The addendum also lists semantic changes made to keep the FIT recommendations updated.
doi:10.4103/2230-8210.141344
PMCID: PMC4192984
Degludec; exenatide; exenatide LAR; Glucagon like peptide-1 receptor agonists; liraglutide
2.  Cell communication and tissue engineering 
Gap junction intercellular communication (GJIC) is ubiquitous in the majority of cells and is indispensable for proper development and function of most tissues. The loss of gap junction mediated cell to cell communication leads to compromised development in many tissues and organs, and also facilitates tumorigenesis and autonomous cell behavior in cancerous cells. Because cells embedded in an extracellular matrix constantly interact through gap junctions to coordinate normal tissue functions and homeostasis, our group hypothesized that increasing cell to cell communication, via genetically engineering cells to overexpress gap junction proteins, could improve cell signaling and increase differentiation in interior regions of engineered tissue equivalents. In a recent paper,1 we presented a platform to regenerate full 3D equivalents of engineered tissue, providing a strategy to overcome a barrier in regenerative medicine. These findings suggest that both targeted delivery and cell-based strategies can be used as treatments to enhance communication in 3D living tissue.2 In this addendum, we address the effects of extracellular calcium (Ca2+e) on intracellular calcium (Ca2+i), GJIC and osteogenic differentiation under conditions in which bone marrow stromal cells (BMSCs) also exhibit higher cell-to-cell communication. As a key secondary messenger in many biological processes, the levels of Ca2+e and Ca2+i play a role in cell differentiation and may be a tunable signal in tissue regeneration. Higher cell-to-cell communication was achieved by both genetically engineering cells to overexpress connexin 43 (Cx43) and by a high density cell seeding technique, denoted micromass seeding (MM). The results presented in this addendum show that the intensity and duration of a second messenger, like calcium, can be augmented in a platform that enables higher cell-to-cell communication. The ability to modulate calcium signaling, combined with our previous approaches to modulate GJIC, may have an impact on tissue regeneration and therapies for communication incompetent cells, such as those associated with heart disease and certain types of cancer.
PMCID: PMC2881242  PMID: 20539784
connexin 43 (Cx43); gap junction intercellular communication (GJIC); calcium; micromass cultures; Bone
3.  Addendum: First injection technique recommendations for patients with diabetes, Forum for Injection Techniques India 
The forum for injection techniques, India recommendation, the first ever in the country on insulin injcetion techniques, have covered the science and the art of insulin injection technique in an exhaustive manner. However, a few gaps were identified in the document, which are addressed in the current addendum. This article focuses on insulin injection technique in special clinical situations, including geriatric people, women in pregnancy and those with dermatological or surgical disease who live with diabetes. The addendum also covers salient features of administration of insulin using the insulin pump.
doi:10.4103/2230-8210.122611
PMCID: PMC3872676
Dermatology; geriatric diabetes; insulin pump; pregnancy; surgical disease
4.  A randomized phase II study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma: A North Central Cancer Treatment Group Study, N0775 
Cancer  2012;119(3):586-592.
Background
Increasing evidence shows chemotherapy in combination with VEGF inhibition is a clinically active therapy for patients with metastatic melanoma (MM).
Methods
A phase II trial was conducted in chemotherapy naïve patients with unresectable stage IV MM who were randomized to temozolomide (200 mg/m2 on d. 1–5) and bevacizumab (10mg/kg IV d. 1 and 15) every 28 days (Regimen temozolomide/bevacizumab [TB]) or nab-paclitaxel (100mg/m2 [80 mg/m2 post addendum 5-secondary to toxicity] days 1, 8 and 15), bevacizumab (10mg/kg on days 1 and 15), and carboplatin (AUC 6 day 1 [ AUC 5 post addendum 5]) every 28 days (Regimen ABC). Accrual goal was 41 patients per regimen. The primary aim of this study was to estimate progression-free survival rate at 6 months (PFS6) in each regimen. A regimen would be considered promising if its PFS6 rate was > 60%.
Results
Ninety-three eligible patients (42 TB and 51 ABC) were enrolled. The majority of patients had M1c disease (20- TB & 26 ABC). The median PFS and overall survival (OS) times with ABC were 6.7 months and 13.9 months, respectively. Median PFS time and median OS with TB were 3.8 months and 12.3 months, respectively. The most common severe toxicities (≥grade 3) in both regimens were cytopenias, fatigue, and thrombosis. Among the first 41 patients enrolled onto each regimen, PFS6 rate was 32.8% (95% CI: 21.1–51.2%) for TB and 56.1% (90% CI: 44.7–70.4%) for ABC.
Conclusions
The addition of bevacizumab to nab-paclitaxel and carboplatin shows promising activity despite tolerability issues.
doi:10.1002/cncr.27760
PMCID: PMC4089063  PMID: 22915053
metastatic melanoma; chemotherapy; VEGF inhibition; combination therapy; unresectable metastatic melanoma
5.  The tolerance of the Arabidopsis defense hormone receptor mutant coi1 against the vascular pathogen Verticillium longisporum is not due to increased levels of the active hormone jasmonoyl-isoleucine 
Plant Signaling & Behavior  2013;8(11):e27008.
Verticillium longisporum is a soil-borne vascular pathogen found primarily on oilseed rape in Northern Europe. Infection of the model plant Arabidopsis thaliana can be achieved under laboratory conditions. In the article related to this addendum, we have shown that Arabidopsis dde2–2 mutants that are compromised in their ability to synthesize the defense hormone jasmonoyl-isoleucine (JA-Ile) are slightly more susceptible than wild-type. Contrary to the expectation that hormone biosynthesis mutants and their respective receptor mutants should have the same phenotype, we found that plants that lack the JA-Ile receptor CORONATINE INSENSITIVE1 (COI1) are more tolerant to the disease. This addendum addressed the question whether the increased JA-Ile levels found in coi1 are responsible for its tolerance phenotype. Based on the evidence that the JA-Ile-deficient dde2–2 coi1-t double mutant is as tolerant as coi1-t, we conclude that increased JA-Ile levels do not protect Arabidopsis against the fungus in the absence of COI1.
doi:10.4161/psb.27008
PMCID: PMC4091333  PMID: 24300304
COI1; jasmonoyl-isoleucine; coi1-mediated tolerance; Verticillium longisporum
6.  How Does Joint Remodeling Work? 
Cell Adhesion & Migration  2007;1(2):102-103.
Remodeling of joints is a key feature of inflammatory and degenerative joint disease. Bone erosion, cartilage degeneration and growth of bony spurs termed osteophytes are key features of structural joint pathology in the course of arthritis, which lead to impairment of joint function. Understanding their molecular mechanisms is essential to tailor targeted therapeutic approaches to protect joint architecture from inflammatory and mechanical stress. This addendum summarizes the new insights in the molecular regulation of bone formation in the joint and its relation to bone resorption. It describes how inflammatory cytokines impair bone formation and block the repair response of joints towards inflammatory stimuli. It particularly points out the key role of Dickkopf-1 protein, a regulator of the Wingless signaling and inhibitor of bone formation. This new link between inflammation and bone formation is also crucial for explaining the generation of osteophytes, bony spurs along joints, which are characterized by new bone and cartilage formation. This mechanism is largely dependent on an activation of wingless protein signaling and can lead to complete joint fusion. This addendum summarized the current concepts of joint remodeling in the limelight of these new findings.
PMCID: PMC2633978  PMID: 19262161
joint remodeling; arthritis; bone formation; bone erosion; osteoblasts; osteoclasts; Dickkopf; wingless proteins
7.  E2F and retinoblastoma related proteins may regulate GL1 expression in developing Arabidopsis trichomes 
Plant Signaling & Behavior  2008;3(6):420-422.
This is an addendum to our recent paper published in The Plant Journal (52:352–61). The major findings were: (1) trichomes on the leaves of gl3-sst sim double mutants developed as large multi-cellular clusters whereas wild type trichomes are composed of single cells; (2) ectopic CYCD3;1 expression in gl3-sst trichomes also resulted in trichome cluster formation; and (3) that GL1 expression is prolonged in the gl3-sst sim trichome clusters. This addendum shows that ectopic CYCD3;1 expression in gl3-sst also enhanced GL1 expression. An analysis of the GL1 promoter found two overlapping potential E2F binding sites in a region of the promoter known to be essential for GL1 function. This finding indicates that GL1 may be directly regulated by the activity of a CYCD3/CDKA complex that phosphorylates E2F-RB bound to the GL1 promoter.
PMCID: PMC2634322  PMID: 19704586
plant cell cycle; endoreduplication; glabra1; plant development
8.  Low phosphate signaling induces changes in cell cycle gene expression by increasing auxin sensitivity in the Arabidopsis root system 
Plant Signaling & Behavior  2009;4(8):781-783.
Lateral root development is an important morphogenetic process in plants, which allows the modulation root architecture and substantially determines the plant's efficiency for water and nutrient uptake. Postembryonic root development is under the control of both endogenous developmental programs and environmental stimuli. Nutrient availability plays a major role among environmental signals that modulate root development. Phosphate (Pi) limitation is a constraint for plant growth in many natural and agricultural ecosystems. Plants posses Pi-sensing mechanisms that enable them to respond and adapt to conditions of limited Pi supply, including increased formation and growth of lateral roots. Root developmental modifications are mainly mediated by the plant hormone auxin. Recently we showed that the alteration of root system architecture under Pi-starvation may be mediated by modifications in auxin sensitivity in root cells via a mechanism involving the TIR1 auxin receptor. In this addendum, we provide additional novel evidence indicating that the low Pi pathway involves changes in cell cycle gene expression. It was found that Pi deprivation increases the expression of CDKA, E2Fa, Dp-E2F and CyCD3. In particular, E2Fa, Dp-E2F and CyCD3 genes were specifically upregulated by auxin in Pi-deprived Arabidopsis seedlings that were treated with the auxin transport inhibitor NPA, indicating that cell cycle modulation by low Pi signaling is independent of auxin transport and dependent on auxin sensitivity in the root.
PMCID: PMC2801399  PMID: 19820337
phosphate signaling; auxin transport; auxin sensitivity; roots
9.  Recreational Viagra Use and Sexual Risk among Drug Abusing Men 
Until recently, the Viagra connection to HIV was anchored in older adults. However, CDC investigation showed stability in 50+ HIV diagnoses on the heels of upward trends in risk indicators among men who have sex with men (MSM) and substance abusing populations. Signs have increasingly pointed to recreational drug use among younger populations, to which Viagra is being added to the mix. Currently, the field is still locating the substance abuse, sexual risk and age-related dimensions of Viagra misuse. Recent studies identify it primarily as substance abuse, but the majority reports a combination of risky sex and risky drug use. At the very least, Viagra appears related to the enhancement of sexual experience or performance, even when it is used to compensate for erectile dysfunction caused by other drugs—either illicit or prescribed (e.g., antidepressants and highly active antiretroviral therapy or HAART). The populations studied, however, frequently have limited the generalizability of findings. This report analyzes the relationship among Viagra, Club Drugs and HIV sexual risk behavior in drug using men with a sample diverse in sexual orientation and demographic scope. Participants were 640 males recruited from three HIV prevention programs in Los Angeles County. Mean age was 43.97 years, ranging from 18.7 to 70.3 with almost 25% over 50. Sexual orientation was 79% heterosexual, 8% bisexual and 12% gay. Racial composition was 45% white, 35% black and 19% Hispanic. NIDA’s Risk Behavior Assessment and a Club Drug/Viagra addendum were used to collect socio-demographic, substance use and sexual risk data. Multiple logistic regression models were constructed along with chi-square tests of association and some t-tests. White race was a major risk factor. No age effect was found. MSM were more likely to use Viagra. Insertive anal sex was a significant co-factor among heterosexual Viagra users involved in transactional sex with women. In the overall sample and the subsets of heterosexual, MSM, younger and older men, predictive models all identified club or designer drugs as significant co-factors in the use of Viagra. Different patterns of drug co-factors were observed for each subset. We detected consistent positive associations between the use of Viagra and the use of amphetamines immediately before or during sex. Viagra use has moved into a new generational context and now complicates the sexual risk and intervention equations for all men, particularly MSM as well as more hidden subgroups.
PMCID: PMC1716731  PMID: 17191089
Viagra; drug abuse; sexual risk; sexual behaviour
10.  Fine-tuning of early events in the jasmonate response 
Plant Signaling & Behavior  2008;3(10):846-847.
Jasmonates (JAs) control many aspects of plant defense and development, for instance by inhibiting growth and eliciting secondary metabolism. The mechanisms by which JAs regulate these processes are currently under intensive investigation. Examination of transcriptional changes upon methyl jasmonate (MeJA) perception in a fast-growing Arabidopsis thaliana cell suspension culture revealed a quick and direct dual effect of JAs on the plant's cellular processes. Simultaneously, JA-elicited Arabidopsis cells activated phenylpropanoid metabolism and repressed cell cycle progression. Early JA response genes were predominantly implicated in transcriptional regulation and JA biosynthesis. In two parallel screens, we identified both early responsive transcriptional activators (ORA47 and MYC2) and transcriptional repressors (STZ/ZAT10 and AZF2) that putatively regulate the expression of the JA biosynthesis gene LOX3. In this addendum, we provide additional data demonstrating that MYC2, STZ/ZAT10 and AZF2 might also control the expression of JAZ1/TIFY10a that encodes a key repressor in the JA signaling cascade.
PMCID: PMC2816351  PMID: 20140232
jasmonate; transcriptional regulation; JAZ; TIFY; MYC2; C2H2 zinc fingers; lipoxygenase
11.  Expression, purification and preliminary X-ray crystallographic analysis of the chicken MHC class I molecule YF1*7.1. Addendum 
Addendum to Hee et al. [Acta Cryst. (2009), F65, 422–425].
Additional funding is acknowledged by the authors of Hee et al. [Acta Cryst. (2009), F65, 422–425].
doi:10.1107/S1744309110001089
PMCID: PMC2815697
YF1*7.1; chicken Rfp-Y; MHC class I antigens; addendum
12.  Zinc transport mediated by barley ZIP proteins are induced by low pH 
Plant Signaling & Behavior  2009;4(9):842-845.
It is estimated that nearly 50% of the world's population is at risk of zinc (Zn) deficiency. The challenge is therefore to increase the Zn content in edible plant parts in order to improve the nutritional value of staple foods. We recently reported the identification and characterization of three barley genes encoding zinc transport proteins belonging to the ZIP protein family. These proteins are believed to be involved in cellular uptake of Zn2+. In this addendum, the Zn2+ transport capacity of ZIP proteins isolated from barley roots was investigated in response to various pH levels. We show that a lowering of pH induces a better growth at low Zn2+ concentrations of yeast cells expressing ZIP proteins. However, no significant change in transport capacity (Vmax) could be observed for HvIRT1, whereas lowering of pH from 5.5 to 4.2 increased the Vmax value with 64% for HvZIP5. These results indicate that proton activity has an important role in regulating the Zn2+ transport capacity of Zn2+ specific ZIP transport proteins. This information will increase the understanding of ZIP proteins and facilitate engineering of genotypes able to grow efficiently on marginal soils.
PMCID: PMC2802790  PMID: 19847115
ZIP proteins; barley; zinc transport; pH
13.  Does nitric oxide play a pivotal role downstream of auxin in promoting crown root primordia initiation in monocots? 
Plant Signaling & Behavior  2009;4(10):999-1001.
Increasing instances prove that nitric oxide (NO) plays a significant role in mediating root growth and development, and it is reported that NO acts as a messenger and mediates the auxin-induced adventitious roots (AR) developing process in cucumber explants. Compared with the current understanding of AR development in dicots, knowledge of the molecular and physiological mechanisms of crown root (CR) development in monocots is limited, and the roles of NO in CR initiation and development are still far from clear. Our recent studies demonstrate that a critical concentration of endogenous NO is indispensable for CR primordia initiation, the reduction of endogenous NO content blocks CR primordia initiation and decreases CR number in rice seedlings. In this addendum, Base on the results of our studies and previous reports, we supposed that CR formtion in monocots and AR formtion in dicots possible take part in the same NO signaling pathway, althoug in dicots, AR are formed under unusual circumstances and belong to the abnormal developmental program, and in monocot cereals, CR are genetically determined roots and belong to the normal developmental program of cereals. At last, we advanced a proposed schematic model showing the NO signaling pathway of CR emergence in monocots.
PMCID: PMC2801373  PMID: 19826236
adventitious root; auxin; crown root; nitric oxide; primordia initiation; signal molecule
14.  Regulation of cell cycle regulators by environmental signals during growth-dormancy cycle of trees 
Plant Signaling & Behavior  2009;4(10):959-961.
Climate change such as changing temperature and increasing concentrations of atmospheric CO2, are likely to drive significant modifications in forests. While many studies have demonstrated the responses and adoptions of tree to fluctuations in climatic and environmental conditions, the impact of environmental signals on trees is complex and poorly understood with respect to the molecular biology in context of the seasonal change of environmental signals. This addendum is focused on the impact of environmental signals on growth-dormancy cycle of trees growing in temperate regions, especially the regulation of cell cycle regulators by temperature and photoperiod. In addition, the plant hormone control of growth-dormancy cycle of trees and cell cycle regulators in the cambium is also discussed.
PMCID: PMC2801361  PMID: 19826221
cell cycle regulators; environmental signals; growth-dormancy cycle of trees; temperature
15.  ARF, autophagy and tumor suppression 
Autophagy  2009;5(3):397-399.
Autophagy plays a critical role in the initiation and progression of tumors. The exact nature of this role, however, is complex. Autophagy is suppressive to tumor initiation, and reduces genomic instability. Genes with key roles in autophagy are mutated in human cancer, and knock-out mice for certain autophagy genes are predisposed to cancer. Conversely, established tumors appear to utilize autophagy in order to survive periods of metabolic or hypoxic stress. Consistent with this, small molecule inhibitors of autophagy like chloroquine are effective anti-cancer agents for certain tumor types. The consensus appears to be that autophagy suppresses tumor initiation, but promotes the survival of established tumors. But this premise may be over-simplified. Several groups have recently shown that the ARF tumor suppressor can induce autophagy. While some groups have found that ARF-mediated autophagy is cytotoxic to tumor cells, we have shown that ARF’s autophagy function may promote the survival and progression of certain tumors. We have previously shown that silencing ARF limits autophagy and the development of p53-null lymphomas. In this addendum, we show this is not true for primary p53-null sarcoma cells. Rather, ARF-silencing enhances sarcoma development. These data suggest that the survival-benefit of ARF, and possibly also of autophagy, may be restricted to certain tumor types.
PMCID: PMC2667648  PMID: 19221462
p14ARF; mitochondria; tumor suppression; autophagy
16.  Comment on Anderson and Ones (in press) 
European journal of personality  2008;22(2):151-156.
The “erratum and addendum” by Anderson and Ones (this issue) does not state unambiguously that participants’ HPI scale scores were incorrectly matched with their scores on the other inventories’ scales, nor does it mention the existence of other errors in the scoring of the OPQ and BPI scales. We demonstrate these errors, and we recommend the retraction of the articles by Anderson and Ones (2003) and Ones and Anderson (2002).
doi:10.1002/per.663
PMCID: PMC2860968  PMID: 20431717
17.  Differentially regulated kinases and phosphatases in roots may contribute to inter-cultivar difference in rice salinity tolerance 
Plant Signaling & Behavior  2009;4(12):1163-1165.
Rice is the second most important cereal crop in the world but its production suffers from saline environments in many areas since it is one of the most salt sensitive crops. However, the large divergence in tolerance between rice cultivars can be exploited to gain insights into mechanisms of salinity tolerance, for example by carrying out comparative transcriptomics studies. We recently showed that specific transporters in roots of the tolerant rice cultivar FL478 are differentially regulated compared to their counterparts in the more sensitive IR29 cultivar and that this may contribute to the observed lower Na+ influx, reduced Na+ translocation to the shoot, and lower Na+:K+ ratio observed in FL478. In this addendum we further evaluated some of the regulatory genes that are potentially important in the modulation of membrane transporters involved in rice cation homeostasis.
PMCID: PMC2819446  PMID: 20514236
phosphorylation; rice; transciptomics
18.  Sumoylation and abscisic acid signaling 
Plant Signaling & Behavior  2009;4(12):1176-1178.
The conjugation of small ubiquitin-related modifier (SUMO) to substrates (sumoylation) is one of posttranslational modification systems in eukaryotes. Sumoylation plays an important role in the regulation of environmental stress response, biotic stress response, and flowering control in plants. Covalent SUMO conjugation requires an E1/E2/E3 enzyme, and SUMO E3 ligase SIZ1 is essential for these regulations. This addendum summarizes our recent study in which it has been established that in Arabidopsis, SUMO E3 ligase SIZ1 negatively controls abscisic acid (ABA) signaling through the sumoylation of ABI5. The conjugation of SUMO to ABI5 represses its activity and also prevents ABI5 from undergoing degradation.
PMCID: PMC2819450  PMID: 20514240
seed germination; seedling growth; SUMO; sumoylation; SIZ1; signal transduction
19.  Role of the fourth membrane domain of the NR2B subunit in the assembly of the NMDA receptor 
Channels (Austin, Tex.)  2008;2(3):159-160.
N-methyl-D-aspartate (NMDA) receptors play crucial roles in excitatory synaptic transmission as well as in excitotoxicity. A growing body of evidence suggests that the regulation of both subunit composition and the number of NMDA receptors reaching the surface membrane are tightly regulated. Recently, we have shown that the third membrane domains (M3) of both NR1 and NR2B subunits contain endoplasmic reticulum (ER) retention signals that prevent the unassembled subunits from leaving the ER. Furthermore, these membrane domains together with NR1 M4 are necessary for negating the ER retention signals found in M3 of NR1 and NR2B. In this addendum, we present new electrophysiological data showing that mutation of the HLFY motif, located immediately after M4 of the NR2B subunit, abolishes the surface trafficking of full-length NR1/NR2B complexes (supporting previous immunofluorescent experiments from our lab); however, the deletion of the NR2B C-terminus including the HLFY motif did not affect the formation of functional receptors when two pieces of the NR2B subunit, NR2B truncated before M4 and NR2B M4, were co-expressed together with the NR1 subunit. These observations will help to uncover the processes involved in the assembly of NR1 and NR2 subunits into functional NMDA receptors.
PMCID: PMC2889170  PMID: 18836292
ER retention; glutamate receptor; ion channel; masking; patch-clamp; recombinant; subunit assembly
20.  Vipp1 and PspA 
The Vesicle Inducing Protein in Plastids 1 (Vipp1) was suggested to be involved in thylakoid membrane formation in both chloroplasts and cyanobacteria. The protein shows sequence homology to the Phage Shock Protein A (PspA) from bacteria, and both proteins have similar secondary structures. 2D-structures of PspA and of Vipp1 have been determined by electron microscopy in the recent years. Both PspA and Vipp1 form large homooligomeric rings with high molecular masses but their ring dimensions differ significantly. Furthermore, Vipp1 forms rings with different rotational symmetries whereas PspA appears to form rings with singular rotational symmetry. In this article addendum we compare the structures of PspA and Vipp1. Furthermore, we suggest a spatial structural model of the observed Vipp1 rings.
PMCID: PMC2889975  PMID: 20585511
PspA; Vipp1; ring; structure; function
21.  Emerging roles of collapsin response mediator proteins (CRMPs) as regulators of voltage-gated calcium channels and synaptic transmission 
Presynaptic N-type voltage-gated Ca2+ channels (Cav2.2) form part of an extensive macromolecular complex in the presynaptic terminal. Regulation of Cav2.2 is achieved via protein-protein interactions within the terminal and can directly impact transmitter release which is dependent on Ca2+ influx via these Cav2.2. We recently identified a novel Cav2.2 interacting partner—the collapsin response mediator protein (CRMP).1 CRMPs are a family of five proteins implicated in signal transduction of neurite outgrowth and axonal guidance. We showed that CRMP-2, a wellstudied member of this family, interacted with Cav2.2 via direct binding to cytoplasmic loops of Cav2.2. Depolarization enhanced the interaction. Further studies revealed that CRMP-2 facilitated an increase in Cav2.2 current density by inserting more Cav2.2 at the cell surface. As a consequence of CRMP-2-mediated increase in Ca2+ influx, release of the excitatory neurotransmitter glutamate was also increased. CRMP-2 localized to synapses where, surprisingly, its overexpression increased synapse size. We hypothesize that the CRMP-2-calcium channel interaction represents a novel mechanism for modulation of Ca2+ influx into nerve terminals and, hence, of synaptic strength. In this addendum, we further discuss the significance of this study and the possible implications to the field.
PMCID: PMC2889978  PMID: 20585514
axonal outgrowth; CRMP-2; growth cone; presynaptic calcium channels; surface trafficking; Cav2.2; synaptic transmission
22.  Arabidopsis SUMO E3 ligase AtMMS21 regulates root meristem development 
Plant Signaling & Behavior  2010;5(1):53-55.
The small ubiquitin modifier (SUMO) conjugation/deconjugation is an important regulatory progress in plant development and responses to abiotic stresses. However, much less is known about the roles of sumoylation in plant root development. Cytokinin and auxin play crucial roles in determining the balance between cell proliferation and cell differentiation in Arabidopsis roots. The SUMO E3 ligase AtMMS21 is a homologue of human NSE2/MMS21, which modulates DNA damage and DNA repair in human cells. This addendum summarizes our recent paper on the AtMMS21 mediating cytokinin signaling to regulate the root meristem cell proliferation. The mms21-1 roots had reduced responses to exogenous cytokinins and decreased expression of the cytokinin-induced genes ARR3, ARR4, ARR5 and ARR7, compared with the wild type. Furthermore, the expression of CRE1 and ARR1, which are both the receptor and positive regulator of cytokinin signaling, was also reduced in the mms21-1 mutant plants.
PMCID: PMC2835958  PMID: 20592809
Arabidopsis thaliana; AtMMS21; cytokinin; root meristem; SUMO E3 ligase
23.  The role of toxin A and toxin B in Clostridium difficile-associated disease 
Gut microbes  2010;1(1):58-64.
Recently, we constructed and characterized isogenic tcdA and tcdB mutants of a virulent Clostridium difficile strain and used a hamster model of disease to demonstrate that toxin B, not toxin A, is essential for virulence of this emerging pathogen. Earlier studies had shown that purified toxin A alone was able to induce C. difficile disease pathology and that purified toxin B was not effective unless it was co-administered with toxin A, suggesting that the toxins act synergistically. In this addendum we discuss this paradigm-shifting conclusion in the context of current strain epidemiology, particularly with respect to naturally occurring toxin A-negative, toxin B-positive isolates and the NAP1/027 epidemic isolates. The role of toxin receptors and how variant toxins might exert their effects is also discussed in relation to the published data. We conclude that it is critical to use the natural infection process to dissect the role of toxins in disease, and that future studies are contingent on such work. The impact and importance of animal models of C. difficile virulence are therefore considered within this frame of reference.
doi:10.4161/gmic.1.1.10768
PMCID: PMC2906822  PMID: 20664812
Clostridium difficile; infection; toxin; nosocomial; colitis; antibiotic
24.  RADICAL-INDUCED CELL DEATH1 and SIMILAR TO RCD ONE1 and the stress-induced morphogenetic response 
Plant Signaling & Behavior  2010;5(2):143-145.
Plants exposed to abiotic stress show a range of morphogenetic responses, sometimes termed the stress-induced morphogenetic response (SIMR). SIMR is principally composed of three components: inhibition of cell elongation, alterations in cell differentiation, and stimulus of cell division in localized areas. An explanation proposed for SIMR has been increased accumulation of reactive oxygen species (ROS) and alterations in hormone signaling. Mutations in the Arabidopsis thaliana RADICAL-INDUCED CELL DEATH1 (RCD1) gene have altered abiotic stress responses and ROS accumulation. Even in the absence of exogenous stress, these plants show many morphological changes also seen in SIMR. In the September issue of Plant Physiology we reported an in depth analysis of the phenotype of rcd1-3 plants as well as the phenotype of a mutations in the previously uncharacterized paralog of RCD1, SIMILAR TO RCD ONE1 (SRO1). sro1-1 plants have mild morphological changes and abiotic stress response defects while rcd1-3; sro1-1 double mutant plants have severe developmental defects, including less cell elongation. In this Addendum, we hypothesize that rcd1, sro1 and rcd1; sro1 mutant plants are under constitutive stress, and that this stress is responsible for at least some of the developmental defects seen in these plants.
PMCID: PMC2884118  PMID: 20009514
RCD1; SRO1; Arabidopsis thaliana; reactive oxygen species; stress-induced morphogenetic response; PARP
25.  The PP2C-SnRK2 complex 
Plant Signaling & Behavior  2010;5(2):160-163.
The phytohormone abscisic acid (ABA), an important bioactive compound in plants, is implicated in several essential processes such as development and the abiotic stress response. Many components have been reported to have roles in these processes. Although 2C-type protein phosphatases (PP2C) and SNF1-related protein kinases2 (SnRK2) family are known to be important signal mediators, the molecular mechanisms by which these components regulate the ABA signaling pathway have not been elucidated. Recent identification of soluble ABA receptors, PYR/PYL/RCAR, has provided a major breakthrough in understanding the signaling mechanisms of ABA and revealed the importance of PP2Cs. In addition, the physical, biochemical and physiological connections between PP2C and SnRK2 have been clearly demonstrated. Taken together, the molecular basis of the major ABA signaling pathway has been established, from perception to gene expression. In this addendum, we discuss this emerging ABA signaling pathway, which has a conventional protein phosphorylation/dephosphorylation regulatory circuit and consider its physiological and functional relevance.
PMCID: PMC2884124  PMID: 20023393
ABA receptor; abscisic acid; PP2C; signal transduction; SnRK2; plant hormone; phosphoarylation

Results 1-25 (315)