ROS-Mediated ABA Signaling

In plants, reactive oxygen species (ROS) are short-lived molecules produced through various cellular mechanisms in response to biotic and abiotic stimuli. ROS function as second messengers for hormone signaling, development, oxygen deprivation, programmed cell death, and plant–pathogen interactions. Recent research on ROS-mediated responses has produced stimulating findings such as the specific sources of ROS production, molecular elements that work in ROS-mediated signaling and homeostasis, and a ROS-regulated gene network (Neill et al., Curr Opin Plant Biol 5:388–395, 2002a; Apel and Hirt, Annu Rev Plant Biol 55:373–399, 2004; Mittler et al., Trends Plant Sci 9:490–498, 2004; Mori and Schroeder, Plant Physiol 135:702–708, 2004; Kwak et al., Plant Physiol 141:323–329, 2006; Torres et al., Plant Physiol 141:373–378, 2006; Miller et al., Physiol Plant 133:481–489, 2008). In this review, we highlight new discoveries in ROS-mediated abscisic acid (ABA) signaling. Drs. Daeshik Cho and June M. Kwak are the corresponding authors for this paper.     

Kinetic models of photosystem II should accommodate the effect of donor side quenching on variable chlorophyll <Emphasis Type="Italic">a</Emphasis> fluorescence in the microseconds time range

Quantitative data on laser flash-induced variable fluorescence in the 100 ns to 1 ms time range (Belyaeva et al. in Photosynth Res 98:105–119, 2008) confirming those of others (Steffen et al. in Biochemistry 40:173–180, 2001, Biochemistry 44:3123–3132, 2005; Belyaeva et al. in Biophysics 51(6):976–990, 2006), need a substantial correction with respect to magnitude of the normalized variable fluorescence associated with single turnover-induced charge separation in RCs of PS II. Their data are conclusive with the involvement of donor side quenching, the release of which occurs with a rate constant in the range of tens of ms⁻¹, and presumed to be associated with reduction of Y_\textz ⁺ Y_{\text{z}}^{ + } by the OEC.     

Chaperone receptors: guiding proteins to intracellular compartments

Despite mitochondria and chloroplasts having their own genome, 99% of mitochondrial proteins (Rehling et al., Nat Rev Mol Cell Biol 5:519–530, 2004) and more than 95% of chloroplast proteins (Soll, Curr Opin Plant Biol 5:529–535, 2002) are encoded by nuclear DNA, synthesised in the cytosol and imported post-translationally. Protein targeting to these organelles depends on cytosolic targeting factors, which bind to the precursor, and then interact with membrane receptors to deliver the precursor into a translocase. The molecular chaperones Hsp70 and Hsp90 have been widely implicated in protein targeting to mitochondria and chloroplasts, and receptors capable of recognising these chaperones have been identified at the surface of both these organelles (Schlegel et al., Mol Biol Evol 24:2763–2774, 2007). The role of these chaperone receptors is not fully understood, but they have been shown to increase the efficiency of protein targeting (Young et al., Cell 112:41–50, 2003; Qbadou et al., EMBO J 25:1836–1847, 2006). Whether these receptors contribute to the specificity of targeting is less clear. A class of chaperone receptors bearing tetratricopeptide repeat domains is able to specifically bind the highly conserved C terminus of Hsp70 and/or Hsp90. Interestingly, at least of one these chaperone receptors can be found on each organelle (Schlegel et al., Mol Biol Evol 24:2763–2774, 2007), which suggests a universal role in protein targeting for these chaperone receptors. This review will investigate the role that chaperone receptors play in targeting efficiency and specificity, as well as examining recent in silico approaches to find novel chaperone receptors.     

Thalamocortical transformations of periodic stimuli: the effect of stimulus velocity and synaptic short-term depression in the vibrissa–barrel system

Recent works on the response of barrel neurons to periodic deflections of the rat vibrissae have shown that the stimulus velocity is encoded in the corti cal spike rate (Pinto et al., Journal of Neurophysiology, 83(3), 1158–1166, 2000; Arabzadeh et al., Journal of Neuroscience, 23(27), 9146–9154, 2003). Other studies have reported that repetitive pulse stimulation produces band-pass filtering of the barrel response rate centered around 7–10 Hz (Garabedian et al., Journal of Neurophysiology, 90, 1379–1391, 2003) whereas sinusoidal stimulation gives an increasing rate up to 350 Hz (Arabzadeh et al., Journal of Neuroscience, 23(27), 9146–9154, 2003). To explore the mechanisms underlying these results we propose a simple computational model consisting in an ensemble of cells in the ventro-posterior medial thalamic nucleus (VPm) encoding the stimulus velocity in the temporal profile of their response, connected to a single barrel cell through synapses showing short-term depression. With sinusoidal stimulation, encoding the velocity in VPm facilitates the response as the stimulus frequency increases and it causes the velocity to be encoded in the cortical rate in the frequency range 20–100 Hz. Synaptic depression does not suppress the response with sinusoidal stimulation but it produces a band-pass behavior using repetitive pulses. We also found that the passive properties of the cell membrane eventually suppress the response to sinusoidal stimulation at high frequencies, something not observed experimentally. We argue that network effects not included here must be important in sustaining the response at those frequencies.

More discussions for granger causality and new causality measures

Granger causality (GC) has been widely applied in economics and neuroscience to reveal causality influence of time series. In our previous paper (Hu et al., in IEEE Trans on Neural Netw, 22(6), pp. 829–844, 2011), we proposed new causalities in time and frequency domains and particularly focused on new causality in frequency domain by pointing out the shortcomings/limitations of GC or Granger-alike causality metrics and the advantages of new causality. In this paper we continue our previous discussions and focus on new causality and GC or Granger-alike causality metrics in time domain. Although one strong motivation was introduced in our previous paper (Hu et al., in IEEE Trans on Neural Netw, 22(6), pp. 829–844, 2011) we here present additional motivation for the proposed new causality metric and restate the previous motivation for completeness. We point out one property of conditional GC in time domain and the shortcomings/limitations of conditional GC which cannot reveal the real strength of the directional causality among three time series. We also show the shortcomings/limitations of directed causality (DC) or normalize DC for multivariate time series and demonstrate it cannot reveal real causality at all. By calculating GC and new causality values for an example we demonstrate the influence of one of the time series on the other is linearly increased as the coupling strength is linearly increased. This fact further supports reasonability of new causality metric. We point out that larger instantaneous correlation does not necessarily mean larger true causality (e.g., GC and new causality), or vice versa. Finally we conduct analysis of statistical test for significance and asymptotic distribution property of new causality metric by illustrative examples.     

Bone tissue,lyophilized and stored at room temperature for 15 days or more,is not capable of transmitting HIV,HCV or HBV

Over the past 57 years, 17 recipients of frozen bone have been infected with: HIV (Centers for Disease Control and Prevention in Morb Mortal Wkly Rep MMWR 37(39):597–599, 1988; Li et al. in J Formos Med Assoc 100(5):350–351, 2001; Simonds et al. in NEJM 326(11):726–732, 1992; Schratt et al. in Unfallchirurg 99(9):679–684, 1996); HCV (Eggen and Nordbo in NEJM 326(6):411, 1992; Conrad et al. in J Bone Joint Surg Am 77:214–224, 1995; Trotter in J Bone Joint Surg Am 851(11):2215–2217, 2003; Tugwell et al. in Ann of Internal Med 143(9):648–654, 2005); or HBV (Shutkin in J Bone Joint Surg Am 36:160–162, 1954). However, bone, lyophilized and stored at room temperature, has never transmitted these viral diseases. A literature review was undertaken to determine whether there is any evidence that lyophilized bone is capable of transmitting HIV, HCV and HBV.     

The synaptonemal complex and meiotic recombination in humans: new approaches to old questions

Meiotic prophase serves as an arena for the interplay of two important cellular activities, meiotic recombination and synapsis of homologous chromosomes. Synapsis is mediated by the synaptonemal complex (SC), originally characterized as a structure linked to pairing of meiotic chromosomes (Moses (1958) J Biophys Biochem Cytol 4:633–638). In 1975, the first electron micrographs of human pachytene stage SCs were presented (Moses et al. (1975) Science 187:363–365) and over the next 15 years the importance of the SC to normal meiotic progression in human males and females was established (Jhanwar and Chaganti (1980) Hum Genet 54:405–408; Pathak and Elder (1980) Hum Genet 54:171–175; Solari (1980) Chromosoma 81:315–337; Speed (1984) Hum Genet 66:176–180; Wallace and Hulten (1985) Ann Hum Genet 49(Pt 3):215–226). Further, these studies made it clear that abnormalities in the assembly or maintenance of the SC were an important contributor to human infertility (Chaganti et al. (1980) Am J Hum Genet 32:833–848; Vidal et al. (1982) Hum Genet 60:301–304; Bojko (1983) Carlsberg Res Commun 48:285–305; Bojko (1985) Carlsberg Res Commun 50:43–72; Templado et al. (1984) Hum Genet 67:162–165; Navarro et al. (1986) Hum Reprod 1:523–527; Garcia et al. (1989) Hum Genet 2:147–53). However, the utility of these early studies was limited by lack of information on the structural composition of the SC and the identity of other SC-associated proteins. Fortunately, studies of the past 15 years have gone a long way toward remedying this problem. In this minireview, we highlight the most important of these advances as they pertain to human meiosis, focusing on temporal aspects of SC assembly, the relationship between the SC and meiotic recombination, and the contribution of SC abnormalities to human infertility.The synaptonemal complex–50 years     

Temperature controls a latitudinal gradient in the proportion of watershed nitrogen exported to coastal ecosystems

Increased export of biologically available nitrogen (N) to the coastal zone is strongly linked to eutrophication, which is a major problem in coastal marine ecosystems (NRC (2000) Clean Coastal Waters: Understanding and Reducing the Effects of Nutrient Pollution. National Academy Press, Washington, DC; Bricker et al. (1999) National Estuarine Eutrophication Assessment. Effects of nutrient enrichment in the nation’s estuaries. NOAA-NOS Special Projects Office, Silver Spring, MD). However, not all of the nitrogen input to a watershed is exported to the coast (Howarth et al. (1996) Biogeochemistry 35:75–139; Jordan and Weller (1996) Bioscience 46:655–664). Global estimates of nitrogen export to coasts have been taken to be 25% of watershed input, based largely on northeastern U.S. observations (Galloway et al. (2004) Biogeochemistry 70:153–226; Boyer et al. (2006) Global Biogeochem Cycle 20:Art. No. GB1S91). We applied the N budgeting methodology developed for the International SCOPE Nitrogen project (Howarth et al. (1996) Biogeochemistry 35:75–139; Boyer et al. (2002) Biogeochemistry 57:137–169) to 12 watersheds in the southeastern U.S., and compared them with estimates of N export for 16 watersheds in the northeastern U.S. (Boyer et al. (2002) Biogeochemistry 57:137–169). In southeastern watersheds, average N export was only 9% of input, suggesting the need for downward revision of global estimates. The difference between northern and southern watersheds is not a function of the absolute value of N inputs, which spanned a comparable range and were positively related to export in both cases. Rather, the proportion of N exported was significantly related to average watershed temperature (% N export = 58.41 e^{−0.11 * temperature}; R ² = 0.76), with lower proportionate nitrogen export in warmer watersheds. In addition, we identified a threshold in proportionate N export at 38°N latitude that corresponds to a reported breakpoint in the rate of denitrification at 10–12°C. We hypothesize that temperature, by regulating denitrification, results in increased proportionate N export at higher latitudes. Regardless of the mechanism, these observations suggest that temperature increases associated with future climate change may well reduce the amount of nitrogen that reaches estuaries, which will have implications for coastal eutrophication.     

Genome-wide meta-analysis for rheumatoid arthritis

Meta-analysis is being increasingly used as a tool for integrating data from different studies of complex phenotypes, because the power of any one study to identify causal loci is limited. We applied a novel meta-analytical approach (Loesgen et al. in Genet Epidemiol 21(Suppl 1):S142–S147, 2001) in compiling results from four studies of rheumatoid arthritis in Caucasians including two studies from NARAC (Jawaheer et al. in Am J Hum Genet 68:927–936, 2001; Jawaheer et al. in Arthritis Rheum 48:906–916, 2003), one study from the UK (MacKay et al. in Arthritis Rheum 46:632–639, 2001) and one from France (Cornelis et al. in Proc Natl Acad Sci USA 95:10746–10750, 1998). For each study, we obtained NPL scores by performing interval mapping (2 cM intervals) using GeneHunter2 (Kruglyak et al. in Am J Hum Genet 58:1347–1363, 1996; Markianos et al. in Am J Hum Genet 68:963–977, 2001). The marker maps differed among the three consortium groups, therefore, the marker maps were aligned after the interval mapping was completed and the NPL scores that were within 1 cM of each other were combined using the method of Loesgen et al. (Genet Epidemiol 21(Suppl 1):S142–S147, 2001) by calculating the weighted average of the NPL score. This approach avoids some problems in analysis encountered by using GeneHunter2 when some markers in the sample are not genotyped. This procedure provided marginal evidence (P<0.05) of linkage on chromosome 1, 2, 5 and 18, strong evidence (P<0.01) on chromosomes 8 and 16, and overwhelming evidence in the HLA region of chromosome 6.     

Leader neurons in leaky integrate and fire neural network simulations

In this paper, we highlight the topological properties of leader neurons whose existence is an experimental fact. Several experimental studies show the existence of leader neurons in population bursts of activity in 2D living neural networks (Eytan and Marom, J Neurosci 26(33):8465–8476, 2006; Eckmann et al., New J Phys 10(015011), 2008). A leader neuron is defined as a neuron which fires at the beginning of a burst (respectively network spike) more often than we expect by chance considering its mean firing rate. This means that leader neurons have some burst triggering power beyond a chance-level statistical effect. In this study, we characterize these leader neuron properties. This naturally leads us to simulate neural 2D networks. To build our simulations, we choose the leaky integrate and fire (lIF) neuron model (Gerstner and Kistler 2002; Cessac, J Math Biol 56(3):311–345, 2008), which allows fast simulations (Izhikevich, IEEE Trans Neural Netw 15(5):1063–1070, 2004; Gerstner and Naud, Science 326:379–380, 2009). The dynamics of our lIF model has got stable leader neurons in the burst population that we simulate. These leader neurons are excitatory neurons and have a low membrane potential firing threshold. Except for these two first properties, the conditions required for a neuron to be a leader neuron are difficult to identify and seem to depend on several parameters involved in the simulations themselves. However, a detailed linear analysis shows a trend of the properties required for a neuron to be a leader neuron. Our main finding is: A leader neuron sends signals to many excitatory neurons as well as to few inhibitory neurons and a leader neuron receives only signals from few other excitatory neurons. Our linear analysis exhibits five essential properties of leader neurons each with different relative importance. This means that considering a given neural network with a fixed mean number of connections per neuron, our analysis gives us a way of predicting which neuron is a good leader neuron and which is not. Our prediction formula correctly assesses leadership for at least ninety percent of neurons.     

1H, 13C and 15N NMR assignments of the C1A and C1B subdomains of PKC-delta

The Protein Kinase C family of enzymes is a group of serine/threonine kinases that play central roles in cell-cycle regulation, development and cancer. A key step in the activation of PKC is translocation to membranes and binding of membrane-associated activators including diacylglycerol (DAG). Interaction of novel and conventional isotypes of PKC with DAG and phorbol esters occurs through the two C1 regulatory domains (C1A and C1B), which exhibit distinct ligand binding selectivity that likely controls enzyme activation by different co-activators. PKC has also been implicated in physiological responses to alcohol consumption and it has been proposed that PKCα (Slater et al. J Biol Chem 272(10):6167–6173, 1997; Slater et al. Biochemistry 43(23):7601–7609, 2004), PKCε (Das et al. Biochem J 421(3):405–413, 2009) and PKCδ (Das et al. J Biol Chem 279(36):37964–37972, 2004; Das et al. Protein Sci 15(9):2107–2119, 2006) contain specific alcohol-binding sites in their C1 domains. We are interested in understanding how ethanol affects signal transduction processes through its affects on the structure and function of the C1 domains of PKC. Here we present the ¹H, ¹⁵N and ¹³C NMR chemical shift assignments for the Rattus norvegicus PKCδ C1A and C1B proteins.     

mGluR7 Genetics and Alcohol: Intersection Yields Clues for Addiction

Development of addiction to alcohol or other substances can be attributed in part to exposure-dependent modifications at synaptic efficacy leading to an organism which functions at an altered homeostatic setpoint. Genetic factors may also influence setpoints and the stability of the homeostatic system of an organism. Quantitative genetic analysis of voluntary alcohol drinking, and mapping of the involved genes in the quasi-congenic Recombinant QTL Introgression strain system, identified Eac2 as a Quantitative Trait Locus (QTL) on mouse chromosome 6 which explained 18% of the variance with an effect size of 2.09 g/kg/day alcohol consumption, and Grm7 as a quantitative trait gene underlying Eac2 [Vadasz et al. in Neurochem Res 32:1099–1112, 100, Genomics 90:690–702, 102]. In earlier studies, the product of Grm7 mGluR7, a G protein-coupled receptor, has been implicated in stress systems [Mitsukawa et al. in Proc Natl Acad Sci USA 102:18712–18717, 63], anxiety-like behaviors [Cryan et al. in Eur J Neurosci 17:2409–2417, 14], memory [Holscher et al. in Learn Mem 12:450–455, 26], and psychiatric disorders (e.g., [Mick et al. in Am J Med Genet B Neuropsychiatr Genet 147B:1412–1418, 61; Ohtsuki et al. in Schizophr Res 101:9–16, 72; Pergadia et al. in Paper presented at the 38th Annual Meeting of the Behavior Genetics Association, Louisville, Kentucky, USA, 76]. Here, in experiments with mice, we show that (1) Grm7 knockout mice express increased alcohol consumption, (2) sub-congenic, and congenic mice carrying a Grm7 variant characterized by higher Grm7 mRNA drink less alcohol, and show a tendency for higher circadian dark phase motor activity in a wheel running paradigm, respectively, and (3) there are significant genetic differences in Grm7 mRNA abundance in the mouse brain between congenic and background mice identifying brain areas whose function is implicated in addiction related processes. We hypothesize that metabotropic glutamate receptors may function as regulators of homeostasis, and Grm7 (mGluR7) is involved in multiple processes (including stress, circadian activity, reward control, memory, etc.) which interact with substance use and the development of addiction. In conclusion, we suggest that mGluR7 is a significant new therapeutic target in addiction and related neurobehavioral disorders.     

Use of weighted reference panels based on empirical estimates of ancestry for capturing untyped variation

Many association methods use a subset of genotyped single nucleotide polymorphisms (SNPs) to capture or infer genotypes at other untyped SNPs. We and others previously showed that tag SNPs selected to capture common variation using data from The International HapMap Consortium (Nature 437:1299–1320, 2005), The International HapMap Consortium (Nature 449:851–861, 2007) could also capture variation in populations of similar ancestry to HapMap reference populations (de Bakker et al. in Nat Genet 38:1298–1303, 2006; González-Neira et al. in Genome Res 16:323–330, 2006; Montpetit et al. in PLoS Genet 2:282–290, 2006; Mueller et al. in Am J Hum Genet 76:387–398, 2005). To capture variation in admixed populations or populations less similar to HapMap panels, a “cosmopolitan approach,” in which all samples from HapMap are used as a single reference panel, was proposed. Here we refine this suggestion and show that use of a “weighted reference panel,” constructed based on empirical estimates of ancestry in the target population (relative to available reference panels), is more efficient than the cosmopolitan approach. Weighted reference panels capture, on average, only slightly fewer common variants (minor allele frequency > 5%) than the cosmopolitan approach (mean r ² = 0.977 vs. 0.989, 94.5% variation captured vs. 96.8% at r ² > 0.8), across the five populations of the Multiethnic Cohort, but entail approximately 25% fewer tag SNPs per panel (average 538 vs. 718). These results extend a recent study in two Indian populations (Pemberton et al. in Ann Hum Genet 72:535–546, 2008). Weighted reference panels are potentially useful for both the selection of tag SNPs in diverse populations and perhaps in the design of reference panels for imputation of untyped genotypes in genome-wide association studies in admixed populations. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

100% complete assignment of non-labile 1H, 13C, and 15N signals for calcium-loaded calbindin D9k P43G

Here we present the 100% complete assignment chemical shift of non-labile ¹H, ¹⁵N and ¹³C nuclei of Calbindin D_9k P43G. The assignment includes all non-exchangeable side chain nuclei, including ones that are rarely reported, such as LysNζ as well as the termini. NMR experiments required to achieve truly complete assignments are discussed. To the best of our knowledge our assignments for Calbindin D_9k extend beyond previous studies reaching near-completeness (Vis et al. in Biochem 33:14858–14870, 1994; Yamazaki et al. in J Am Chem Soc 116:6464–6465, 1994; Yamazaki et al. in Biochem 32:5656–5669, 1993b).     

Parameter Identifiability and Estimation of HIV/AIDS Dynamic Models

We use a technique from engineering (Xia and Moog, in IEEE Trans. Autom. Contr. 48(2):330–336, 2003; Jeffrey and Xia, in Tan, W.Y., Wu, H. (Eds.), Deterministic and Stochastic Models of AIDS Epidemics and HIV Infections with Intervention, 2005) to investigate the algebraic identifiability of a popular three-dimensional HIV/AIDS dynamic model containing six unknown parameters. We find that not all six parameters in the model can be identified if only the viral load is measured, instead only four parameters and the product of two parameters (N and λ) are identifiable. We introduce the concepts of an identification function and an identification equation and propose the multiple time point (MTP) method to form the identification function which is an alternative to the previously developed higher-order derivative (HOD) method (Xia and Moog, in IEEE Trans. Autom. Contr. 48(2):330–336, 2003; Jeffrey and Xia, in Tan, W.Y., Wu, H. (Eds.), Deterministic and Stochastic Models of AIDS Epidemics and HIV Infections with Intervention, 2005). We show that the newly proposed MTP method has advantages over the HOD method in the practical implementation. We also discuss the effect of the initial values of state variables on the identifiability of unknown parameters. We conclude that the initial values of output (observable) variables are part of the data that can be used to estimate the unknown parameters, but the identifiability of unknown parameters is not affected by these initial values if the exact initial values are measured with error. These noisy initial values only increase the estimation error of the unknown parameters. However, having the initial values of the latent (unobservable) state variables exactly known may help to identify more parameters. In order to validate the identifiability results, simulation studies are performed to estimate the unknown parameters and initial values from simulated noisy data. We also apply the proposed methods to a clinical data set to estimate HIV dynamic parameters. Although we have developed the identifiability methods based on an HIV dynamic model, the proposed methodologies are generally applicable to any ordinary differential equation systems.