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Articles, Cellular/Molecular
Modulation of the Cold-Activated Channel TRPM8 by Lysophospholipids and Polyunsaturated Fatty Acids
David A. Andersson, Mark Nash and Stuart Bevan
Journal of Neuroscience 21 March 2007, 27 (12) 3347-3355; DOI: https://doi.org/10.1523/JNEUROSCI.4846-06.2007
David A. Andersson
Mark Nash
Stuart Bevan
We investigated the role of phospholipase A2 (PLA2) and the effects of PLA2 products (polyunsaturated fatty acids and lysophospholipids) on the cold-sensitive channel transient receptor potential (melastatin)-8 (TRPM8), heterologously expressed in Chinese hamster ovary cells. TRPM8 responses to cold and the agonist icilin were abolished by inhibitors of the calcium-independent (iPLA2) form of the enzyme, whereas responses to menthol were less sensitive to iPLA2 inhibition. Inhibition of PLA2 similarly abolished the cold responses of the majority of cold-sensitive dorsal root ganglion neurons. The products of PLA2 had opposing effects on TRPM8. Lysophospholipids (LPLs) (lysophosphatidylcholine, lysophosphatidylinositol, and lysophosphatidylserine) altered the thermal sensitivity of TRPM8, raising the temperature threshold toward normal body temperature. Polyunsaturated fatty acids (PUFAs), such as arachidonic acid, inhibited the activation of TRPM8 by cold, icilin, and menthol. The relative potencies of lysophospholipids and PUFAs are such that lysophosphatidylcholine is able to modulate TRPM8 in the presence of an equimolar concentration of arachidonic acid. Positive modulation by LPLs provides a potential physiological mechanism for sensitizing and activating TRPM8 in the absence of temperature variations.
TRPM8
lysophospholipid
icilin
Members of the transient receptor potential (TRP) family of ion channels function as sensors of the physical and chemical environment (Clapham, 2003). Light, chemicals, touch, temperature, and osmolarity are examples of stimuli that can activate different TRP channels. Several TRP channels are thermosensitive and together they confer the ability to sense temperature throughout the range from noxious cold to noxious heat (Jordt et al., 2003; Patapoutian et al., 2003). Thus, TRPV1 is activated near the threshold for noxious heat pain, whereas TRPV2 is stimulated by even higher temperatures (Caterina et al., 1997, 1999). TRPV3 and TRPV4 both sense "warm" temperatures around and below body temperature (Guler et al., 2002; Peier et al., 2002b; Smith et al., 2002; Xu et al., 2002). Transient receptor potential (melastatin)-8 (TRPM8) is activated by cold with a threshold temperature of ∼25°C (McKemy et al., 2002; Peier et al., 2002a; Story et al., 2003).
TRPM8 is expressed in a subpopulation of small cold-sensitive dorsal root ganglion (DRG) neurons consistent with its proposed function as a thermosensor. TRPM8 is also expressed in sensory nerves innervating deeper tissues that, under normal circumstances, never experience the low temperatures (<25°C) necessary to activate the channel. In these tissues, it is likely that TRPM8 is activated or modulated by endogenous agonists or mechanisms other than temperature.
The activities of many TRP channels are regulated by lipids. PIP2, diacylglycerol, and polyunsaturated fatty acids have been shown to activate or inhibit various TRP channels directly (Runnels et al., 2002; Clapham, 2003; Hardie, 2003; Liu and Liman, 2003; Liu and Qin, 2005; Rohacs et al., 2005). Polyunsaturated fatty acids (PUFAs) and arachidonic acid metabolites constitute a distinct group of lipids that can act as endogenous agonists at some TRP channels. TRPV3 is activated by unsaturated fatty acids, TRPV1 by anandamide and lipoxygenase products, and TRPV4 by epoxyeicosatrienoic acids produced by cytochrome P450 mono-oxygenases (Zygmunt et al., 1999; Hwang et al., 2000; Watanabe et al., 2003; Hu et al., 2006).
In this study, we have examined the role of phospholipase A2 (PLA2) in the activation of TRPM8. All PLA2 enzymes hydrolyze the sn-2 ester of glycerophospholipids to release a free polyunsaturated fatty acid (PUFA) and a lysophospholipid (LPL). Two main groups of intracellular PLA2 enzymes exist, cytosolic PLA2 (cPLA2) and calcium-insensitive PLA2 (iPLA2), also called group IV and group VI PLA2, respectively. Although cPLA2 is selective for phospholipids with arachidonic acid in the sn-2 position, this is not the case for iPLA2, which releases other fatty acids as well (Balsinde and Balboa, 2005). Here we report the discovery of a key role for iPLA2 in the regulation of TRPM8 and show that lysophospholipids, produced by PLA2 activity, positively modulate TRPM8 and can act as endogenous agonists to activate the channel at normal physiological temperatures. In contrast, PUFAs such as arachidonic, eicosapentaenoic, and docosahexaenoic acid inhibit TRPM8. Although the two groups of PLA2 products exert opposing modulatory effects on TRPM8, the net balance of equimolar concentrations of the PLA2 products favors TRPM8 activation. These findings introduce lysophospholipids as novel modulators of thermosensitive TRP channel activity.
Cell culture.
Chinese hamster ovary (CHO) cells expressing mouse TRPM8 (Peier et al., 2002a) were grown in MEM α medium without ribonucleosides and deoxyribonucleosides, supplemented with penicillin (100 U/ml), streptomycin (100 μg/ml), l-glutamine (2 mm), FCS (10%), and hygromycin B (200 μg/ml).
DRG cultures.
DRG neurons were prepared from adult (∼200 g) male or female Wistar rats as described previously (Bevan and Winter, 1995). Rats were asphyxiated with CO2 as approved by the United Kingdom Home Office, and spinal ganglia were removed aseptically from all levels of the spinal cord. Ganglia were incubated in 0.125% collagenase type IV (Worthington Biochemical, Lakewood, NJ) for 3 h in DMEM (Invitrogen, Paisley, UK) with 2 mm l-glutamine at 37°C in a humidified incubator gassed with 5% CO2 in air. Neurons were dissociated mechanically by trituration with a flame-polished Pasteur pipette. The DRG neurons were centrifuged through 2 ml of 15% bovine albumin in DMEM media, and the pellet was resuspended in DMEM with 10% fetal bovine serum (Invitrogen), 2 mm l-glutamine, 10 μg/ml penicillin and streptomycin, and 50 ng/ml NGF (Promega, Madison, WI). The neurons were plated onto sterile 13 mm glass coverslips previously coated with 10 μg/ml poly-d-lysine and 5 μg/ml laminin and maintained at 37°C in a humidified incubator gassed with 5% CO2.
Imaging of intracellular calcium levels.
CHO cells and DRG neurons were grown on glass coverslips covered with poly-d-lysine and loaded with 2 μm fura-2 AM (Invitrogen, Leiden, The Netherlands) for ∼1 h in the presence of 1 mm probenecid and 0.01% pluronic F-127 at 37°C before the experiments. The dye loading and the subsequent experiments were performed in an assay buffer containing the following (in mm): 140 NaCl, 5 KCl, 10 glucose, 10 HEPES, 2 CaCl2, and 1 MgCl2, buffered to pH 7.4 (NaOH). Compounds were applied to cells by local microperfusion of solution through a fine tube placed very close to the cells being studied. The temperature of the perfusion buffer was controlled by a regulated Peltier device (Marlow Industries, Dallas, TX) and monitored by a thermocouple positioned in the tip of the perfusion tube. Images of a group of cells were captured every 2 s at 340 and 380 nm excitation wavelengths with emission measured at 520 nm with a microscope-based imaging system (PTI, Birmingham, NJ). Analyses of emission intensity ratios at 340/380 nm excitation (R, in individual cells) were performed with the ImageMaster suite of software.
Neurons in DRG cultures were identified at the end of the experiment by stimulation with an assay buffer supplemented with 50 mm KCl. The resultant depolarization opened voltage-gated calcium channels in the neurons and evoked a calcium influx that was detected by a change in the 340/380 emission ratio.
Electrophysiology.
Cells expressing TRPM8 were grown on glass coverslips covered with poly-d-lysine and studied by whole-cell voltage-clamp recordings using an Axopatch 200A amplifier and pClamp 8.0 software (Molecular Devices, Union City, CA). Experiments were performed at a holding potential of −60 mV, unless stated otherwise. Borosilicate glass pipettes (2–5 MΩ) were filled with the following (in mm): 140 KCl, 0.05 CaCl2, 1 MgATP, 0.1 EGTA, and 10 HEPES. The external assay buffer was the same as described above for imaging of intracellular Ca2+. The cells were superfused locally through a thin tube positioned very close to the cells.
Ninety-six-well plate-based intracellular calcium assays.
In some experiments, changes in intracellular calcium were determined in TRPM8 expressing CHO cells grown in 96-well black-walled plates (Costar, Cambridge, MA) using a Flexstation (Molecular Devices). Cells were loaded with fura-2 AM as described above and washed with assay buffer. Assays were performed at 30°C. Basal emission ratios (340/380 nm) were measured for 17 s, and then compounds were injected, and the change in dye emission ratio was determined after 60 s.
The specific cPLA2 inhibitor N-{(2S,4R)-4-(biphenyl-2-ylmethyl-isobutyl-amino)-1-[2-(2,4-difluorobenzoyl)-benzoyl]-pyrrolidin-2-ylmethyl}-3-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-phenyl]acrylamide HCl (cPI), N-(p-amylcinnamoyl)anthranilic acid (ACA), 5,8,11,14-eicosatetraynoic acid (ETYA), and E-6-(bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one (BEL) were obtained from Calbiochem (La Jolla, CA). Icilin was obtained from Tocris Bioscience (Ellisville, MO) and arachidonic acid, lysophospholipids, fatty acids, and all other reagents were purchased from Sigma (St. Louis, MO).
Calculation and statistics.
Data are presented as means ± SEM for the number of experiments indicated (n). Curve fitting was performed in Origin 7 (OriginLab, Northampton, MA). Statistical significance was calculated using an unpaired t test or ANOVA, followed by Bonferroni's post hoc test.
Inhibition of PLA2 prevents activation of TRPM8
We used fura-2 to monitor the effect of PLA2 inhibition on [Ca2+]i responses induced by cold, icilin, and menthol in CHO cells expressing TRPM8. The PLA2 inhibitors were applied by superfusion for 2 min before the cells were challenged with cold, menthol, or icilin.
ACA, a cell-permeable, nonselective PLA2 inhibitor, completely inhibited responses to stimulation with icilin (1 μm) or cold (cold ramp to 13°C) and reduced the amplitude of [Ca2+]i responses evoked by 1 mm menthol (Fig. 1). ACA does not distinguish between different PLA2 isoforms. To identify the enzyme targeted by ACA in CHO cells, we examined the effects of PLA2 inhibitors selective for iPLA2 and cPLA2 on TRPM8 activity. A potent and selective cell-permeable cPLA2 inhibitor, cPI (100 nm) (Seno et al., 2000), had no effect on the responses to menthol, icilin, or cold (Table 1). In contrast, 45 min of incubation with a selective irreversible and cell-permeable iPLA2 inhibitor, BEL (20 μm), almost completely inhibited the [Ca2+]i responses evoked by cold and icilin but only produced a small inhibition of the response to menthol (Table 1). ETYA, a general inhibitor of arachidonic acid metabolism, and the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA), are two compounds that also inhibit PLA2 (Lanni and Becker, 1985). Both compounds had the same profile as BEL and ACA. ETYA (10 μm) and NDGA (20 μm) effectively inhibited the responses to icilin and cold but had only a small effect on the response to menthol (Table 1). Because TRPM8 was sensitive to BEL and nonselective inhibitors of PLA2, but not to the cPLA2 selective inhibitor cPI, our results strongly implicate iPLA2 in the maintenance and regulation of TRPM8 activity.
The PLA2 inhibitor ACA inhibits TRPM8. A–C, Cold (A), icilin (B), and menthol (C) evoked large [Ca2+]i responses in CHO cells expressing TRPM8. Superfusing the cells with ACA before agonist challenge abolished responses induced by a cold ramp (A) and icilin (B) and significantly reduced responses to menthol (C). Traces are the mean responses of groups of cells monitored individually (n = 28–41). Veh, Vehicle; temp, temperature.
Effect of PLA2inhibitors on [Ca2+]iresponses evoked by cold, icilin, and menthol
Menthol-induced [Ca2+]i responses showed a different sensitivity to PLA2 inhibition than those evoked by icilin and cold (Table 1). Conditions that completely inhibited responses to cold and icilin (ACA, 10 μm; BEL, 20 μm for 45 min) only partially reduced the responses to menthol. This parallels previous findings that responses to menthol are less sensitive to the intracellular Ca2+ concentration and pHi than those elicited by cold and icilin (Andersson et al., 2004; Chuang et al., 2004). To characterize the abilities of PLA2 inhibitors to inhibit the responses evoked by menthol and icilin in more detail, we constructed inhibition–response curves studying the effects of different concentrations of ACA and BEL on TRPM8 responses evoked by fixed concentrations of agonist (Fig. 2). In these experiments, we used concentrations of icilin (40 nm) and menthol (40 μm) that elicit submaximal responses of similar amplitude (∼EC80 concentrations). ACA and BEL completely inhibited responses to icilin (IC50 values of 0.46 ± 0.1 and 8.6 ± 2 μm, respectively), whereas much higher concentrations of these inhibitors were required to inhibit the [Ca2+]i responses to menthol (IC50 values of 6.9 ± 3 and 30 ± 4 μm with ACA and BEL).
ACA and BEL concentration–response curves. A, B, The nonselective PLA2 inhibitor ACA (A) and the selective iPLA2 inhibitor BEL (B) concentration-dependently reduced [Ca2+]i responses evoked by icilin and menthol. Both inhibitors were significantly more potent against icilin than menthol. Data points are mean ± SEM measured in triplicates, and the data shown are representative of n = 3 separate experiments.
Although BEL is regularly used to determine the involvement of iPLA2, it is also a well documented inhibitor of phosphatidic acid phosphohydrolase 1 (PAP-1). We addressed the possibility that the effect of BEL was attributable to PAP-1 inhibition by using propranolol, which at high concentrations is an inhibitor of PAP-1 (Fuentes et al., 2003). At a relevant high concentration (250 μm), propranolol failed to inhibit [Ca2+]i responses to cold or icilin, ruling out the involvement of PAP-1 (data not shown).
Effects of PLA2 inhibition on native TRPM8 in DRG neurons
TRPM8 is expressed in sensory neurons in trigeminal and dorsal root ganglia. In good agreement with previous studies (Peier et al., 2002a), we found that 6.8% of DRG neurons in culture were sensitive to stimulation with menthol and 9% to icilin (Table 2). Cold stimulated a slightly larger cell population (11.6%) (Table 2). Two distinct populations of cold-sensitive DRG neurons have been described based on their sensitivity or insensitivity to menthol and differences in threshold temperatures (Story et al., 2003; Babes et al., 2004). Story et al. (2003) found that menthol-sensitive neurons had a temperature threshold of ∼23°C, whereas the threshold for the menthol-insensitive neurons was lower, ∼15°C. A smaller difference in temperature threshold for menthol-sensitive (24.9°C) and menthol-insensitive (22.9°C) neurons was noted by Babes et al. (2004). Nevertheless, both studies showed that TRPM8 expression was associated with higher temperature thresholds. We noted that treatment with either ACA (10 μm) or BEL (25 μm) reduced the population of cold-sensitive neurons to <4%. ACA and BEL also significantly reduced the number of menthol-sensitive neurons and inhibited the effect of icilin almost completely (Table 2). The percentage of cold-sensitive neurons that were resistant to inhibition of PLA2 was the same as the percentage of menthol-insensitive, cold-sensitive neurons. Interestingly, the temperature threshold for cold-sensitive DRG neurons after PLA2 inhibition was 4–7°C lower than in the overall population (Table 2). Thus, our data are consistent with the conclusion that cold and icilin activation of TRPM8 in DRG neurons, as in CHO cells, was abolished by iPLA2 inhibition and that the small remaining population of (non-TRPM8) cold-sensitive DRG neurons require lower temperatures for activation. In addition, menthol responses in DRG neurons were more resistant to PLA2 inhibition than those to cold and icilin, similar to our results in CHO cells.
PLA2 inhibitors reduce the proportion of cold-sensitive cultured DRG neurons
TRPM8 is inhibited by polyunsaturated fatty acids
All PLA2 enzymes hydrolyze the sn-2 ester of glycerophospholipids to release a free fatty acid and a LPL. Arachidonic acid and endogenous metabolites of arachidonate are known activators of other thermosensitive TRP channels: TRPV1, TRPV3, TRPV4, and TRPA1 (Zygmunt et al., 1999; Hwang et al., 2000; Watanabe et al., 2003; Bandell et al., 2004; Hu et al., 2006). TRPM2, the ion channel with greatest homology to TRPM8, can also be activated by arachidonic acid (Hara et al., 2002; Togashi et al., 2006). We therefore examined the potential regulatory role of arachidonic acid and related fatty acids on TRPM8.
Unlike the findings with other thermosensitive TRP channels, arachidonic acid reduced the cold, icilin, and menthol sensitivity of CHO cells expressing TRPM8. Arachidonic acid (10 μm) depressed the [Ca2+]i responses to icilin (1 μm) by 97 ± 1% and to cold stimulation (measured at 13°C) by 96 ± 2%. A smaller (76 ± 2%), but highly significant, inhibition of the response to 100 μm menthol was recorded in the presence of arachidonic acid (Fig. 3). To discern whether the observed inhibition was specific for arachidonic acid (20:4) or a more general property of polyunsaturated fatty acids, we also tested the effects of 10 μm eicosapentaenoic acid (20:5) and docosahexaenoic acid (22:6) on the cold responses of TRPM8. The results shown in Figure 4 clearly demonstrate that cold activation of TRPM8 was almost completely inhibited by all three polyunsaturated fatty acids. This was also the case with [Ca2+]i responses induced by menthol (50 μm) and icilin (1 μm). IC50 values determined from concentration–response curves showed that all three fatty acids inhibit responses to icilin and menthol with similar potencies (Table 3). The results suggest that TRPM8 can be regulated by variations in the cellular concentrations of PUFAs.
Arachidonic acid inhibits TRPM8. A, B, Arachidonic acid (AA) (10 μm) almost completely inhibited [Ca2+]i responses induced by a cold ramp from 37°C to 12°C (A), 100 nm icilin (B), and 100 μm menthol (C). Each trace is the average response from a group of cells (n = 25–50) monitored individually. The average peak response amplitude of experiments like those in A–C is shown in D (n = 3–4).
TRPM8 is sensitive to polyunsaturated fatty acids. A, B, Eicosapentaenoic acid (EPA) (A) and docosahexaenoic acid (DOHA) (B) prevented [Ca2+]i responses to stimulation with a cold ramp (from 37°C to 12°C). The traces in A and B are average responses in groups of cells (n = 25–50 cells). C, Average peak amplitude from experiments like those in A, B, and Figure 3A [the arachidonic acid (AA) data are the same as those shown in Fig. 3D].
IC50 values for polyunsaturated fatty acids as inhibitors of icilin and menthol
Lysophosphospholipids stimulate TRPM8
PLA2 liberates LPLs as well as fatty acids, and iPLA2 has been suggested to regulate store-operated calcium entry through production of LPLs (Smani et al., 2004). Because we discovered that inhibition of iPLA2 as well as treatment with arachidonic acid prevented activation of TRPM8, we next tested whether LPLs could act as endogenous activators or positive modulators of TRPM8 (Fig. 5).
TRPM8 is activated by lysophospholipids. A, Lysophosphatidylcholine elicited [Ca2+]i responses in cells expressing TRPM8 but not in untransfected CHO cells. After a longer initial delay, LPC also activated TRPM8 at 37°C (traces are averages of 25–40 cells monitored individually). B, TRPM8 was activated by lysophospholipids with different head groups. The negatively charged LPI and LPS evoked [Ca2+]i responses of amplitude similar to the zwitterionic LPC, whereas SPC was much less effective (all at a concentration of 3 μm). Experiments were performed at 29°C, and the data in B are mean ± SEM of the number of experiments indicated.
Application of 3 μm lysophosphatidylcholine (LPC) (16:0) produced large [Ca2+]i responses in CHO cells transfected with TRPM8 (Δratio 2.6 ± 0.2) but not in untransfected control cells (Δratio 0.1 ± 0.1). LPC (3 μm) was able to induce [Ca2+]i responses in TRPM8 at 37°C although with a longer delay than at 29°C (Fig. 5A). PLA2 activity in vivo is likely to produce a mixture of LPLs with different head groups and acyl chains. To explore whether LPLs containing head groups with different properties can activate TRPM8, we used the anionic lysophosphatidylinositol (LPI) and lysophosphatidylserine (LPS) as well as the zwitterionic LPC. We also tested the effects of a sphingolipid, sphingosyl-phosphorylcholine (SPC). The [Ca2+]i responses evoked by 3 μm LPI and LPS were similar to those elicited by LPC, whereas SPC was much less effective at this concentration (Fig. 5B). We were unable to construct full agonist concentration–response curves for the lysophospholipids acting at TRPM8 because higher concentrations (≥5 μm) evoked a second type of cellular [Ca2+]i response that was evident in untransfected CHO cells (data not shown). Nevertheless, we noted that lower (1 and 2 μm) concentrations of LPC, LPI, and LPS produced mean [Ca2+]i responses that showed little difference in amplitude between the lipid species (data not shown). We investigated the importance of the fatty acid chain length for LPL activity by examining the effects of an LPC with a much shorter acyl chain (6:0). This short-chain LPC failed to activate TRPM8 even at concentrations as high as 40 μm (data not shown).
To further demonstrate that LPC can activate TRPM8, we compared the single-channel activity evoked by menthol and LPC in cell-attached membrane patches (Fig. 6). Before application of menthol or LPC, no channel activity was recorded in the patches. Application of menthol (50 μm) to the cells elicited brief channel openings within a few seconds with a mean single-channel current amplitude of 2.9 ± 0.1 pA at +60 mV. LPC (3 μm) evoked channel activity similar to menthol (single-channel current amplitude 3.1 ± 0.1 pA at +60 mV) but after a much longer delay (Fig. 6C,D). This delay may reflect slow penetration of the cell membrane attributable to the amphiphathic character of LPC. In a different set of experiments, LPC (3 μm) was applied in cell-attached mode, and when channel activity had developed, we excised the membrane patch in the continued presence of LPC to record channel activity in the inside-out patch configuration (Fig. 6G). After excision, P(open) decreased as reported previously (Reid and Flonta, 2002; Voets et al., 2004), but there was still marked channel activity in the patch, suggesting that LPC is able to activate TRPM8 in a membrane-delimited manner.
Menthol and LPC stimulate TRPM8 single-channel activity. A, C, In cell-attached patches, menthol (50 μm) stimulated channel activity within a few seconds of application. B, D, LPC (3 μm) elicited very similar single-channel activity but after a much longer initial delay. E, F, All point histograms from traces recorded in the presence of menthol (E) and LPC (F) show a similar distribution. Both histograms have been fitted with the sum of three Gaussian functions. G, Traces were recorded in cell-attached configuration in the absence and presence of LPC (3 μm). When channel activity had developed, the patch was excised to inside-out configuration. After patch excision, the channel activity stimulated by LPC persisted. Data were recorded at a holding potential of +60 mV. Veh, Vehicle.
Menthol potentiates the effect of cooling on TRPM8 by raising the temperature threshold (Reid and Flonta, 2001; McKemy et al., 2002; Peier et al., 2002a). We found that this was also the case with LPC. LPC strongly potentiated the whole-cell currents and [Ca2+]i responses evoked by cooling. In electrophysiology experiments, the threshold for temperature activation in the presence of 3 μm LPC was raised by 3–5°C and the amplitude of the cold-evoked current at 11°C was increased sixfold from 190 ± 90 to 1280 ± 190 pA (Fig. 7A). The effect of LPC on [Ca2+]i responses elicited by cooling was much more dramatic. Application of increasing concentrations of LPC (1–3 μm) progressively elevated the temperature activation threshold. At 3 μm, TRPM8 was activated at 37°C in many cells. The augmented cold-activated [Ca2+]i responses in the presence of LPC were caused by a calcium influx through TRPM8 because it was dependent on the presence of extracellular Ca2+ (Fig. 7B). In addition, LPC had no effect on [Ca2+]i in untransfected CHO cells (data not shown).
LPC modulates the cold sensitivity of TRPM8. A, LPC potentiates responses to cold by increasing the current amplitude and by shifting the activation threshold to higher temperatures (temp). B, Pseudocolored ratio images from [Ca2+]i imaging experiments illustrating that LPC shifts the temperature activation threshold of TRPM8 closer to physiologically relevant values. No response was seen in the absence of extracellular Ca2+.
If PLA2 is important for TRPM8 activation because it produces LPLs, TRPM8 activation by LPLs should be resistant to PLA2 inhibitors. We tested this by applying LPC to cells incubated with 10 μm ACA, a concentration that inhibits responses to menthol, icilin, and cold (Figs. 1, 2). As predicted, ACA failed to affect responses to LPC (Fig. 8A). TRPM8 activation by cold and icilin, but not menthol, is inhibited by reducing the external and internal pH (Andersson et al., 2004). LPC shared this feature because application of LPC (3 μm) failed to evoke any responses in an external solution of pH 6 (Fig. 8A).
LPC is resistant to inhibition of PLA2 but sensitive to low pH. A, The agonist effect of LPC (3 μm) on TRPM8 is unaffected by the presence of 10 μm ACA. Cells incubated in pH 6 for 1 min before stimulation failed to respond to LPC. B, Application of equimolar concentrations of LPC and arachidonic acid (AA) only produced a small reduction of the LPC induced [Ca2+]i responses. C, However, 10 μm arachidonic acid completely inhibited the response to 3 μm LPC. D, Average of the peak amplitude in three determinations in groups of 20–40 cells.
One apparent paradox is that two products of iPLA2 activity, LPLs and PUFAs, have opposite actions on TRPM8. To address this balance between the excitatory and inhibitory effects of LPLs and PUFAs, we applied equimolar concentrations (3 μm) of arachidonic acid and LPC to TRPM8-expressing cells at 31°C. Under these conditions, the amplitude of [Ca2+]i responses induced by LPC were only marginally reduced by the presence of arachidonic acid (Fig. 8B). However, a higher concentration of arachidonic acid (10 μm) was able to inhibit activation of TRPM8 by 3 μm LPC (Fig. 8C).
Our results have demonstrated a key role for iPLA2 in modulating TRPM8 activity. Furthermore, we have demonstrated that the products of PLA2, LPLs and PUFAs, can modulate TRPM8 activity in a reciprocal manner. Lysophospholipids act as positive modulators, whereas PUFAs inhibit TRPM8 activity. Our findings are consistent with a very recent study demonstrating that iPLA2 inhibition partially reduced menthol sensitivity (Abeele et al., 2006). These authors also showed that LPC and LPI could activate TRPM8 expressed in human embryonic kidney 293 cells.
Addition of LPLs raised the thermal threshold for activation so that TRPM8 could be activated by 3 μm LPC at 37°C. LPC had a more dramatic effect on temperature sensitivity in experiments monitoring [Ca2+]i than in voltage-clamp experiments. The reason for this difference is unclear, but it may reflect a loss of a regulatory factor when the intracellular contents are dialysed by the pipette solution in the whole-cell configuration. LPLs acted relatively slowly over many tens of seconds, which suggests that the site of action was intracellular and that activation required translocation across the plasma membrane. The speed of action of LPLs on TRPM8 differs from the almost immediate effects of LPLs on TWIK-related K+ channels (TREK) in which the site of action is thought to be extracellular (Maingret et al., 2000). Because iPLA2 is an intracellular enzyme, the supply of endogenous LPLs to the inner surface of the plasma membrane and subsequent modulation of TRPM8 is likely to be a faster process than suggested by the slow responses to extracellular LPLs observed in our studies.
LPLs are known to modulate the activities of other membrane channels including TREK-1 (Lesage et al., 2000; Maingret et al., 2000) and TRPC5 (Flemming et al., 2006) and can regulate store-operated calcium entry (Smani et al., 2004; Singaravelu et al., 2006). TRPC5 activation by LPLs is also relatively slow and probably requires translocation of the LPL to the internal membrane surface. The absence of LPL responses in untransfected cells at the concentrations studied and the similar properties of LPC- and menthol-activated single-channel currents indicate that the responses to LPLs are mediated by TRPM8 and not by a nonspecific action on membrane lipids (cf. Wilson-Ashworth et al., 2004). How LPLs regulate TRPM8 is unclear. The observation that LPC evoked single-channel current activity was retained when membrane patches were excised into the inside-out configuration suggests that LPLs act on TRPM8 in a membrane-delimited manner. They could have an indirect effect on channel function by interacting with either plasma membrane lipids or channel-associated proteins or a direct effect by binding to TRPM8. We did note that there was no significant difference in the activity of the anionic LPI (16:0) and the zwitterionic LPC (16:0). However, a short-chain species of LPC (6:0) lacked activity altogether, whereas the sphingolipid SPC (16:0) was less active than LPI and LPC. These results suggest that both the length of the fatty acyl chain and the properties of the headgroup influence their actions at TRPM8.
Arachidonic acid and two other PUFAs (docosahexaenoic acid and eicosapentaenoic acid) inhibited TRPM8 with approximately equal potency. This inhibition contrasts with the activation of other thermosensitive TRP channels by PUFAs and arachidonic acid metabolites. Once again it is unclear whether the inhibitory effect of the PUFAs is mediated by an interaction with the plasma membrane or TRPM8 itself.
Continued iPLA2 activity was essential for the maintenance of cold and icilin sensitivity and the ability of these stimuli to activate TRPM8 was lost within minutes of adding the enzyme inhibitors. iPLA2 is considered to have a housekeeping role in cells regulating the turnover of membrane lipids (Balsinde and Balboa, 2005). Consequently, the concentration of LPLs will decrease when iPLA2 is inhibited as the existing LPLs continue to be acylated by acyltransferases. The loss of cold and icilin sensitivity a few minutes after adding PLA2 inhibitors is therefore consistent with a tonic regulatory role for LPLs generated by PLA2.
The pharmacology of icilin and cold differs from that of menthol with respect to pHi sensitivity, dependence on extracellular Ca2+, and iPLA2 activity (Andersson et al., 2004; Chuang et al., 2004) (Fig. 2). LPC shared the pH sensitivity with cold and icilin, suggesting that there is a common step or cofactor requirement for cold, icilin, and LPL activation that is not shared by menthol. Importantly, the action of LPC was resistant to a high concentration of ACA.
LPLs and PUFAs are both released by PLA2, which raised the possibility that the stimulatory effect of LPLs might be cancelled out by the coincident inhibitory action of the PUFAs. However, this scenario is unlikely. First, the reduction in icilin and cold sensitivity after iPLA2 inhibition is consistent with an overall stimulatory effect of the PLA2 products. Second, when we applied LPC and arachidonic acid at equimolar concentrations, LPC still evoked large [Ca2+]i responses. Third, iPLA2 lacks substrate specificity for phospholipids containing particular fatty acids in sn-2 position (unlike cPLA2, which is selective for arachidonic acid) and therefore releases a mixture of saturated and unsaturated fatty acids (Balsinde and Balboa, 2005).
The ability of LPLs to act as positive modulators of TRPM8 function raises the possibility that treatments that increase their concentration will alter the thermal threshold for activation and may even open the channels at normal body temperature (37°C). There is growing evidence that iPLA2 is involved in some cell signaling pathways in addition to its role in homeostatic phospholipid deacylation/reacylation reactions (Smani et al., 2004; Balsinde and Balboa, 2005; Singaravelu et al., 2006). The other major intracellular PLA2 enzyme, cPLA2, is activated by micromolar levels of intracellular calcium and plays a central role in lipid mediator production in pathological conditions, including inflammation, primarily through the release of arachidonic acid and its metabolites (Kita et al., 2006). Although our data indicate that cPLA2 does not have a role in maintaining basal TRPM8 activity, stimuli that stimulate cPLA2 to generate LPLs could sensitize or activate TRPM8.
The phospholipid PIP2 can control the activity and desensitization of TRPM8, and a reduction in the PIP2 levels has been shown previously to explain the rundown of TRPM8 channels in isolated patches (Fig. 6) (Liu and Qin, 2005; Rohacs et al., 2005). This channel rundown and associated decrease in PIP2 concentrations is dramatically accelerated in the presence of Mg2+ (Huang et al., 1998; Liu and Qin, 2005). Because LPC (3 μm)-evoked channel activity was maintained in excised patches in the presence of Mg2+ (1 mm in all recording solutions), PIP2 does not seem to be required for the actions of LPLs on TRPM8.
TRPM8 is a physiological sensor of cold and cool temperatures (McKemy et al., 2002; Peier et al., 2002a). However, temperature alone is unlikely to account for activation of TRPM8 in all tissues because this channel is expressed in sensory nerves innervating visceral organs such as the bladder (Mukerji et al., 2006) and lower gastrointestinal tract (Zhang et al., 2004). TRPM8 is also expressed in non-neuronal cells in prostate and bladder (Tsavaler et al., 2001; Stein et al., 2004). These neurons and non-neuronal cells rarely, if ever, experience the low temperatures generally considered to activate TRPM8 (<25°C). In these cells, endogenous modulators, such as LPLs and PIP2, would raise the temperature threshold so that TRPM8 can operate at physiological body temperatures. These lipid modulators could therefore have two roles: setting the temperature sensitivity of cold receptors in the skin and other tissues that are exposed to the external environment and regulating the activity of TRPM8-expressing neurons that innervate deeper tissues and organs.
This work was supported in part by a grant from the Medical Research Council. We thank Isabelle Garnier for her contribution to the 96-well plate assays.
Correspondence should be addressed to David Andersson, Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London SE1 1UL, UK. david.andersson{at}kcl.ac.uk
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David A. Andersson, Mark Nash, Stuart Bevan
Journal of Neuroscience 21 March 2007, 27 (12) 3347-3355; DOI: 10.1523/JNEUROSCI.4846-06.2007
Cellular/Molecular
mTORC2 Loss in Oligodendrocyte Progenitor Cells Results in Regional Hypomyelination in the Central Nervous System
Identification of the Acid-Sensitive Site Critical for Chloral Hydrate (CH) Activation of the Proton-Activated Chloride Channel
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text:
Dell Latitude 10
Dell Latitude 10 review
The Dell Latitude 10 currently has an Informr score of 7.3 out of 10. This score is based on our evaluation of 6 sources including reviews from users and the web's most trusted critics.
The next wave of consumer-grade tablet computers that will hit the market will be powered by Microsoft's Windows 8 software. And among them is the business-centric Dell Latitude 10, which features a simple all-black design and comes with a 10.1-inch 1366x768 touchscreen display. It's very similar to other Windows 8 tablets in terms of specs. But is there anything that sets it apart from the competition?
At the bottom of this tablet, there's a wide open port that could be mistaken for eSATA or HDMI-out. In reality, this is actually a proprietary port for charging and data that can be used for docking into an accessory for extra functionality. There's also a full-size USB port on one of its sides, right next to the actual port for HDMI. And at the back, a bunch of obvious markings reveal the location of its most distinguishing feature: a fully removable battery.
Because it's removable, users can carry around and use as many extra two-cell or four-cell batteries as they like. Underneath the battery is where compatible SIM cards will reside. The fact that the battery can be easily replaced is definitely a boon for productivity. Speaking of which, this tablet won't be bundled with a keyboard like many other models with Windows 8 Pro. Instead, it can be plugged into an optional dock that gives it four extra USB 2.0 ports and a full-size HDMI port. Dell essentially wants users to bring their own mouse and keyboard.
For it to lack a hardware keyboard is odd since it's a product that's supposed to be designed for business use. While users can get wired or wireless keyboards quite easily, that puts it at a disadvantage when compared with devices that already have bundled keyboard docks. The rest of it is built to standard Windows 8 specs: there's a dual-camera setup, a number of different wireless connectivity options, and support for all existing Windows 7 programs on top of all future modern Windows apps. The removable battery may be a godsend, but more valuable options are available elsewhere.
Need to Know: Dell Latitude 10
1. Comes with a fully removable, user-replaceable battery. (The Good)
2. Runs Microsoft's Windows 8 Pro software, which makes it compatible with not just modern Windows applications from the Windows Store but also all existing Windows 7 desktop programs. (The Good)
3. Does not come with a bundled keyboard dock for easy typing. (The Bad)
4. Uses a proprietary port for charging and data transfer. (The Bad)
8+ MP
30 WHr
The Dell Latitude 10 isn't the most capable Windows 8 tablet we've seen, but if you're after Windows, its wide range of ports and outstanding battery life make it a much better buy than the similarly-priced Lenovo ThinkPad Tablet 2.
- Katharine Byrne, Expert Reviews
Despite the mediocre cameras, sluggish performance and a woeful case, there's plenty to like about the Latitude 10. The huge battery and amazing stamina are enough on their own to justify the asking price of £521. We know of no other device capable of running full Windows software that comes close,...
- Mike Jennings, PC Pro
The Dell Latitude 10 is a capable Windows 8 tablet that's hindered by slow internal components and a design that isn't in balance.
- K. T. Bradford, Digital Trends
Dell's first Windows 8 tablet is an Atom SoC soluton that's aimed primarily at business users thanks to a slew of security options, including TPM, biometrics, SmartCard and encryption software for local and USB drives.
- Serdar Yegulalp, Tech Advisor
Dell's light and flexible Windows 8 tablet is high on business features, but low on price-performance.
- Doug Dineley, InfoWorld
1Does the Dell Latitude 10 have eSATA port?
Dell Latitude 10 Manual (PDF)
The Dell Latitude 10's screen size is 10.1 inches with x pixels resolution.
There is a Atom Z2760 Dual-core 1.8 GHz processor (CPU).
You can take photos or capture video with the tablet's onboard 8+ megapixel camera. There is also a secondary front facing camera with 2+ megapixels resolution.
Internal memory is 64 GB. An external, MicroSD, MicroSDHC expansion slot is available for increased storage capacity.
30WHr
The tablet is powered by a Lithium-Ion (Li-Ion), 30 WHr battery. Dell's performance ratings are 5 days standby time.
Latitude 10 Specs
Compare Windows Tablets
Atom Z2760 Dual-core 1.8 GHz
AC Charger, Manual
Up to: 5 days
Magnesium alloy
3GP / 3GPP, H.264 / AVC, MPEG-4
MIDI, MP3, MP4, eAAC+, AAC+, AAC, WAV
DOC, DOCX, PDF, PPT, PPTX, XLS
Other Names (AKA): Dell T05G
Dell Latitude 10 Reviews
Where to buy Dell Latitude 10
Help inform others by sharing your experience with Dell Latitude 10
This business tablet has great battery life and a wide range of ports
Katharine Byrne from Expert Reviews ( 08 Aug 2013 04:00 )
Delivers unrivalled battery life, and comes with a practical set of peripherals
Mike Jennings from PC Pro ( 03 Apr 2013 04:00 )
Despite the mediocre cameras, sluggish performance and a woeful case, there's plenty to like about the Latitude 10. The huge battery and amazing stamina are enough on their own to justify the asking price of £521. We know of no other device capable of running full Windows software that comes close, and the fact you can buy extra batteries for £56, to swap out when it does eventually run out of juice, turns it into the ultimate road-warrior's tool....
Despite the mediocre cameras, sluggish performance and a woeful case, there's plenty to like about the Latitude 10. The huge battery and amazing stamina are enough on their own to justify the asking price of £521. We know of no other device capable of running full Windows software that comes close, and the fact you can buy extra batteries for £56, to swap out when it does eventually run out of juice, turns it into the ultimate road-warrior's tool.
Add the stylus capability, which places it one step ahead of the Acer Iconia W510, and the desktop dock, which adds to its office-bound appeal, and you have (almost) the perfect mobile workhorse. The Dell Latitude 10 sets a high standard for Windows 8 business devices; we wonder if anything else will be able to compete with it.
Hindered by slow internal components and a design that isn't in balance
K. T. Bradford from Digital Trends ( 11 Mar 2013 04:00 )
The Dell Latitude 10 is a capable Windows 8 tablet that's hindered by slow internal components and a design that isn't in balance. Among the growing crop of Atom-based tablets, the Latitude is among the better devices we've tested. There are still too many drawbacks to fully recommend it ov...More
The Dell Latitude 10 is a capable Windows 8 tablet that's hindered by slow internal components and a design that isn't in balance. Among the growing crop of Atom-based tablets, the Latitude is among the better devices we've tested. There are still too many drawbacks to fully recommend it over the ThinkPad Tablet 2, and even that didn't get a definite thumbs-up. We're still searching for our dream Windows 8 tablet.
Windows 8 tablet meets business PC
Serdar Yegulalp from Tech Advisor ( 08 Mar 2013 05:00 )
Touch tablet meets business desktop
Doug Dineley from InfoWorld ( 28 Feb 2013 05:00 )
The Dell Latitude 10 is a Windows 8 tablet whose optional docking station turns it into a fair substitute for a modest desktop system. The additional business-grade features ramp up the value even further. At the same time, though, the price begins to approach that of better-performing hybrids and Ultrabooks.
It has what it takes to satisfy business users who want to go all day on a charge
Daniel Howley from Laptop Magazine ( 08 Feb 2013 05:00 )
With its amazing battery life, durable soft-touch design, bright display and wide array of optional add-ons, the Windows 8-powered Dell Latitude 10 is a versatile business tablet. Just don't expect a good camera or Ultrabook-like performance. This is more of a PC companion than a full-fledged laptop replacement, though you can certainly get real work done on the go (with the optional pen) and on the big screen (with the dock)....
With its amazing battery life, durable soft-touch design, bright display and wide array of optional add-ons, the Windows 8-powered Dell Latitude 10 is a versatile business tablet. Just don't expect a good camera or Ultrabook-like performance. This is more of a PC companion than a full-fledged laptop replacement, though you can certainly get real work done on the go (with the optional pen) and on the big screen (with the dock).
Among Windows 8 tablets, the Latitude 10 has some pretty stiff competition. The Surface Pro is a lot faster, but ultimately falls flat because of its short battery life. However, the $679 ThinkPad Tablet 2 gives you a place to store its included pen and an optional mobile keyboard dock, making it a better potential laptop replacement. Overall, though, the Dell Latitude 10 has what it takes to satisfy business users who want to go all day on a charge.

redpajama_set_name: RedPajamaCommonCrawl


text:
Confessions of a Mullah Warrior
by Masood Farivar
From an Afghan with deep roots in his nation's history, a courageous and evocative memoir of fleeing the Soviet invasion, coming of age in a madrassa in Pakistan, fighting the Russians with the mujahideen, and moving to America.
Publication Date February 16, 2010
Publication Date March 10, 2009
Born in 1969 in Sheberghan, Afghanistan, Masood Farivar fought in the anti-Soviet resistance in the late 1980s. He then attended Harvard University and received a degree in history.
Read More About Masood Farivar
Masood Farivar was ten years old when his childhood in peaceful and prosperous Afghanistan was shattered by the Soviet invasion of 1979. Although he was born into a long line of religious and political leaders who had shaped his nation's history for centuries, Farivar fled to Pakistan with his family and came of age in a madrassa for refugees. At eighteen, he defied his parents and returned home to join the jihad, fighting beside not only the Afghan mujahideen but also Arab and Pakistani volunteers. When the Soviets withdrew, Farivar moved to America and attended the prestigious Lawrenceville School and Harvard, and ultimately became a journalist in New York.
At a time when the war in Afghanistan is the focus of renewed attention, and its outcome is more crucial than ever to our own security, Farivar draws on his unique experience as a native Afghan, a former mujahideen fighter, and a longtime U.S. resident to provide unprecedented insight into the ongoing collision between Islam and the West. This is a visceral, clear-eyed, and illuminating memoir from an indispensable new voice on the world stage.
Tags Personal Memoirs Middle East/General Islam/General
"In this earnest bildungsroman, Farivar tells the remarkable tale of how he went from Afghan refugee to resistance fighter to Harvard University student. . . . The book succeeds in its in depth exploration of the radicalization of young Muslim men in the 1980s—and Farivar's path away from extremism." —Publishers Weekly
"This invaluable memoir shows the other, non-American side of the Middle Eastern coin. . . . Farivar humanizes the experience for us." —Library Journal
"[An] eye-opening chronicle of cultural exchange." —Kirkus Reviews
Every child who is born is born with a sound nature; it is the parents who make him a Jew or a Christian or a Magian. —Prophet Muhammad
Summer 1974 or 1975—"Agha, Agha," I said excitedly, "look, there's a fish in the river."
It was a late summer afternoon and I was tugging at Agha's shirttail and tiptoeing over a creaky wooden footbridge, exhilarated and frightened by the rush of the muddy Alishang River twenty feet below. Agha was Sufi Ramazan, my father's father and a beloved, gray-bearded elder of our ancestral village of Islamabad in eastern Afghanistan in the province of Laghman. While my cousins called him by the more formal Baba Jee, I for some reason had adopted the term my father and uncles preferred for him: Agha, or Dad.
Ever since he'd given me my name and chanted the azan, the Islamic call to prayer—Allahu Akbar, Allahu Akbar, God is great, God is great—into my ears as an infant, Grandpa Agha had taken a special liking to me, the only son of his oldest son.
I didn't know it at the time, but Agha had decided to introduce me to our ancestral homeland, a world away from my birthplace of Sheberghan in the north. I was happy to get away from Sheberghan for an adventure-filled cross-country trip, but as I clutched Grandpa's shirttail and insisted that I'd spotted a fish in the river, he responded with words that still ring in my ears: "It's a piece of wood, you silly. Now walk carefully or you'll be swimming with the wood."
I was five or six. Agha was pushing seventy and quite fit for his age. He sported a long, neatly trimmed gray beard and a white silk turban. As a district governor in the north of Kabul, he'd earned a reputation for meting out harsh punishments to criminals, but he was kind and gentle with children.
Safely across the river, I let go of Agha and began waltzing through a vast, chest-high field of sugarcane. The village, a cluster of a hundred or so adjoining mud huts and a handful of more sturdily built two-story compounds, lay beyond the field. The sugarcane distracted me. Until Grandpa told me what it was, I thought it was a fatter, thicker variety of nay, a species of bamboo used to make calligraphy pens. When I learned what it was, I started pulling at some of the stalks but they were taller than I and much more stubborn and wouldn't succumb to my efforts. Agha, finding me straining and sweating, pulled out his pocket-knife and cut several canes. I remember proudly carrying the canes over my shoulder and following Agha to one of the compounds to spend the night in a cool room.
Only a few other memories from that visit to Islamabad and other villages in our ancestral province of Laghman have stayed with me: meeting old relatives who wore traditional clothes and spoke in a village dialect I could hardly understand; throwing rocks at sheep and cattle; enjoying local delicacies that I associated with the home of my ancestors—corn bread, fried cheese, brown sugar rocks. And one final image: standing next to a cluster of tombs as Agha lifted his wiry hands in prayer. It wasn't the first time he and I had stopped along our journey to pray for the dead, but these little dirt mounds of tombs weren't ordinary—they belonged to ancestors of ours who had brought Islam to eastern Afghanistan, their history closely tied to that of the country.
I was born and raised in the town of Sheberghan in northern Afghanistan, a very different place from Islamabad. Once a bustling Silk Road trading post, Sheberghan fell on hard times after Genghis Khan's army sacked it in the thirteenth century. While I was growing up in the 1970s, it was something of a backwater town, despite a multiethnic population of some ten thousand. Native Uzbeks predominated, but there were large pockets of Tajiks, Pashtuns, Turkomens, and even nomadic Arabs.
To the other townsfolk, we were Laghmanis—shrewd, industrious, enterprising, and educated. There were so many Laghmanis in Sheberghan that one large neighborhood was informally known as Laghmani Street. Many were close relatives of ours. Grandpa Agha and Grandma Bibi lived there with their three sons, my father, Uncle Khan Agha, and Uncle Agha Shirin. My mother had an older brother and a younger sister as well as two cousins. I knew what to call these close family members, but many others were related to us through blood and family ties so complicated that I sometimes wondered why I called a certain relative a kaakaa, a paternal uncle, rather than a maamaa, a maternal uncle, or a khaala, a maternal aunt, rather than 'ama, a paternal aunt.
To get answers I'd sometimes turn to Ama Koko, my mother's feisty, slightly hunched maternal aunt. Widowed at a young age and childless, Ama Koko never remarried and instead divided her time between her three brothers and their four dozen children. Whenever she visited us, she'd spend much of her time reading the Koran or the book of Hafez, both of which she'd taught to my mother and her siblings. Like many others in the family, I'd occasionally ask her to consult Hafez to divulge my luck. She would open the book at random and start reading at the first verse her eye fell on. The fourteenth-century Persian verses didn't make much sense to me, but Ama Koko always found a way of putting them in terms a child could understand: "Khwaja Hafez sees fabulous fortune in your future."
When I wasn't asking her to read my luck, I'd pester her with questions about our extended family. A great storyteller, she was open to answering any question except the one that hung over her like a dark cloud: how she'd lost her young husband, the son of a powerful khan near Islamabad, in a tribal feud on the day after their wedding. Everything else was fair game.
"So Ama Koko, where were you born?" I'd start.
"Charikar."
Charikar is a small town north of Kabul.
"Charikar? What were you doing in Charikar?"
"My father was a government officer there."
"What was your father's name?"
"Jalilur Rahman."
"What was your grandfather's name?"
"Jamilur Rahman."
"So how are you related to Father?"
"Don't you know?" she'd say, irritated. "Your father is my niece's husband. Don't you see?"
"No, I mean how else are you related?"
"Well, your father is my mother's step-cousin's son. He is also my sister-in-law's son-in-law . . ."
The interrogation would go on and on, sometimes for an hour or more. By her next visit to our house, I'd forget many of the names and subject her to the same battery of questions. But she could never go back more than three generations in the family genealogy.
Years later I came across an old family manuscript that filled in the holes in Ama Koko's narrative. Titled Sifat-naamah-I Darwish Khan-I Ghazi, or The Hagiography of Darwish Khan Ghazi, the hundred-page manuscript opens in 1582, the year Darwish Khan, a middle-aged, fanatical general, led an army from central Asia to the regions surrounding Islamabad, the last non-Muslim pocket of Afghanistan. Accompanying Darwish Khan at the head of the army was his octogenarian spiritual advisor and prayer leader, Sultan Quli, my fourteenth forefather. Sultan Quli was no ordinary mullah. He was the grandson of Khwaja Ubaidullah Ahrar, one of the eminent religious figures of his time and the leader of the Sufi brotherhood known as the Naqshbandiyyah.
Sufism was more than an esoteric spiritual pursuit at the time; it was a way of life for millions and a vehicle by which Islam spread through central and south Asia. Among the many mystical brotherhoods, the Naqshbandiyyah boasted by far the largest following, but what set it apart from other Sufi fraternities was not simply the brotherhood's practice of the "silent prayer" but, more importantly, its close ties to the ruling authorities—first the dynasty founded by Timur in the fourteenth century and later Babur's Moghul empire. Ahrar and his descendents served as powerful, behind-the-scenes advisors of both dynasties. As the late German scholar Annemarie Schimmel put it, Ahrar believed that "to serve the world it is necessary to exercise political power" and to bring political rulers under control so that God's law can be carried out in every aspect of life.
The task facing Darwish Khan's army was daunting: conquer and convert some of the Hindu Kush's toughest and most fiercely independent denizens. Darwish Khan did not hesitate to remind his troops what they were fighting for. As he put it, they were part of a battle between God—the One and the Omnipotent—and the gods and idols of the infidels. As the holy warriors took up position on the bank of the Alishang River, native Pashtun tribesmen began to mobilize. While the infidels sacrificed goats to their gods Pandad, Sharwee, and Laamandee, Darwish Khan summoned Allah's help, assuring his troops that "a man needs courage, not a saber by his side." His army likely took his words seriously, as it was believed that Darwish Khan possessed extraordinary powers, an example of which was the ability to gallop headlong into an encroaching army, slicing dozens of infidels in half "like cucumbers."
A total of sixty-six valleys were conquered and converted, but the expedition wasn't a complete success. While the native Pashtuns submitted to the new faith, another, non-Pashtun tribe, living in adjacent valleys, tenaciously resisted conversion. Originally hailing from the Kandahar region, they had fled north to the Hindu Kush some seven hundred years earlier and spoke in strange tongues, worshipped idols, and sang and danced around their dead. Legend had it that they were descendents of Alexander the Great's army, which explained why many of them had blue eyes and blond hair. The Afghans called the region Kufristan or Kafiristan—the "land of unbelief" or the "land of infidels." For the next three centuries, Kafiristan served as a constant reminder that Darwish Khan's mission to bring Islam to the heathens remained unfulfilled.
As for Darwish Khan and Sultan Quli's descendents and the remnants of the army, they settled on the bank of the Alishang and christened the encampment Islamabad, or City of Islam, and built ties with the newly converted Pashtuns. They intermarried with them, acquired land along the Alishang, and built a thriving settlement in the heart of the Pashtun belt. While many lived off the land, the direct descendents of Sultan Quli continued the religious profession of their ancestors, maintaining mosques, running Koran schools, and appointing prayer leaders and preachers across the region. Religion also ensured that every male in the family, and more than a few females, were literate in the midst of an illiterate society. Seeing it as a source of power, they passed it down to their children, generation after generation.
Meanwhile, in matters both important and banal, tribal ways often prevailed despite the injunctions of Islamic law. Murders went largely unpunished. Few, if any, thieves had their hands chopped off. Women only occasionally received the legal right to inherit property promised to them by the new, egalitarian religion. Much to the shock of Islamabad's piety, some desperate tribesmen traded their wives for cattle. People lived their lives according to the guiding principles of Pashtunwali—the way of the Pashtun. Its main tenets required showing hospitality to all, providing shelter for those in need, and retaliating against those who have wronged you. Pashtunwali made no distinction between rich and poor, landlord and peasant. A khan who looked the wrong way at a peasant's wife could be dragged through the mud, his face blackened, his house burned down, and his family banished. A peasant who stole money could simply pay it back instead of having his hand cut off in accordance with Islam dictates. Everyone, regardless of wealth, was expected to provide lavish hospitality to guests. Khoday dih ghareeb krhee, chaah dih bih ghayratah krhee went one proverb: God made you poor, but who took away your honor?
Darwish Khan's wish for Islamic conversion came to pass in the nineteenth century, due to a fortuitous turn of events. In 1893 the British, who had made two futile attempts to conquer Afghanistan, drew a new border between Afghanistan and British India that came to be known as the Durand Line, named after its architect, Sir Mortimer Durand. Their goal: transform the unruly land of the Afghans—Yaghistan, or the "land of insolence"—into a docile buffer state between Czarist Russia and British India.
The Afghan ruler Abdur Rahman Khan, whom the British had christened the "Iron Amir" because of his ruthless and authoritarian rule, saw this as an opportunity to enlarge his domain. While not a religious fanatic, he quashed an uprising by the minority Shiite Hazaras of central Afghanistan in an effort to rally tribesmen to join his motley army in a jihad against the infidels of Kafiristan. Many panicked Kafirs embraced Islam outright, while other tribal leaders offered to pay tribute to the amir to avert war. This was a tactic they had used for centuries to fight off the spread of Islam, but the amir demanded complete and unconditional conversion.
The campaign to pacify Kafiristan was short-lived but violent. Hundreds were killed while thousands more crossed into the neighboring Chitral region of modern Pakistan, where their Kafir offspring live to this day. When the jihad was over, some sixty thousand infidels had embraced Islam and pledged their allegiance to the amir. With the valley subdued, the amir dispatched an army of mullahs to instruct the converts in the ways of Islam. None other than my maternal great-grandfather, Jalilur Rahman Khan, led a troop of mullahs into the valley, with specially trained barbers circumcising men both young and old in accordance with Islamic tradition. My paternal great-grandfather, also involved in the campaign, took into marriage a young girl from the area. She was one of the many women who were taken as spoils of war from the region, which the warriors renamed Nooristan, or the "land of light."
By the time of Nooristan's conquest, little of Islamabad's past power and prestige was left. In fact, the seat of Islam in eastern Afghanistan had declined into a poor hamlet, overshadowed by the fast-growing Moghul-era frontier town of Jalalabad to the southeast. One by one, the men of Islamabad started leaving in search of economic opportunity elsewhere. Many joined the Iron Amir's bureaucracy, some his military. Grandpa Agha started out as a county clerk before moving on to serve as a district chief in several provinces. His older brother became a provincial police chief in northern Afghanistan. One of the men to strike gold was Grandpa Baba, my maternal grandfather, who was born in 1895. When he was five, he lost his father and was raised along with his two younger brothers and younger sister by his mother and their maternal uncle. He was a mullah who spent most of the first two decades of the last century working as a mirza north of Kabul. Mirza is an ancient Turkic regal title that had only recently come to designate anyone who was either a scribe or a notary. In an attempt to consolidate his power, the amir went beyond his southern tribal base to build a modern state bureaucracy, commissioning a professional army and centralizing the government. Starting with my greatgrandfather Jalilur Rahman, men in my family whose predecessors had for ten generations borne the clerical title mullah now were calling themselves mirzas. It wasn't that these men were abandoning religion. On the contrary, our family maintained two mosques in Islamabad and pilgrims continued to visit the shrine of Darwish Khan and other pioneers. Yet after three centuries of enjoying the power and prestige that came with their position as men of religion and learning, they realized becoming mirzas was a way into the lucrative new world of government service.
As Grandpa Baba mastered the art of official letter writing and penmanship (his apprenticeship required developing a distinct handwriting style—straight alifs, curvy baas, loopy seens—for the entire Arabic alphabet), he seemed destined to follow in his uncle's footsteps. Then, in early 1919, King Habiburrahman Khan was assassinated in his sleep during a hunting expedition near Jalalabad. While the dead monarch's religiously conservative brother and twenty-seven-year-old liberal son jockeyed for possession of the throne, my great-uncle packed up his family and moved back to the secure environs of Islamabad.
Prince Amanullah Khan assumed the throne with the support of the reformist, anticolonialist Young Afghans, who modeled themselves after their Turkish counterparts, and Amanullah soon dispatched a letter to the British viceroy of India declaring Afghanistan's independence. When the British demurred, he did what Afghan rulers had always done when faced with a foreign adversary: he rallied the tribes for a jihad. There followed a series of what Western historians would call "inconclusive skirmishes," fought mostly by southeastern tribesmen, descendents of men converted by Darwish Khan's army. Grandpa Baba spent much of the 1920s as a midlevel district administrator in Laghman. The decade marked one of the most turbulent periods in modern Afghan history, as the young king's effort to transform Afghanistan into a modern secular state, modeled on Mustafa Kemal Atatürk's Turkey, was met with stiff opposition from an alliance of the religious establishment and Pashtun tribes.
By 1929, the liberal regime of King Amanullah was teetering, and Grandpa Baba found himself in the improbable position of defending a monarch who was being accused of heresy. A religiously inspired Tajik movement had overthrown the king, and Grandpa, as a government official and a member of the religious establishment in the Pashtun belt, had sided with a Pashtun general who eventually restored the monarchy. Leaving his post in the Alishang district, Grandpa retired to Islamabad where he reinforced the village's defenses, waiting for months on an enemy force that never materialized. His effort didn't go unrecognized, however. Having struck up a friendship with Mohammad Gul Khan Mohmand, the leader of the Mohmand Pashtuns, one of the tribes fighting the Tajik insurgency, Baba soon found himself in the upper echelons of power as he followed Mohmand to northern Afghanistan.
Running as a surrogate father and son team—Mohmand never sired a son; Grandpa grew up without his father—they governed one of Afghanistan's five administrative regions through much of the 1930s. Mohmand bore the grandiose title of chief executive of the Northern Territories. Grandpa, with his less illustrious title of fourth director, was second in command. Their style of government was ruthless. Justice was swiftly delivered, if only to quash dissent and secure the government's hold on power. To many non-Pashtuns in the north, Mohmand, a self-styled Pashtun nationalist, came to embody the dictatorial rule of the government.
While Mohmand took quarters in the governor's mansion, Grandpa Baba acquired the residence of the former chief executive, an imposing, turn-of-the-century structure of more than two dozen rooms with arched doorways, guesthouses, servants' quarters, stables, and a two-acre pomegranate garden with a large pool surrounded by tall birch trees. Soon Grandpa's clan—his mother, younger sister, two brothers, five wives, and their children—moved in. My mother and her three dozen siblings and cousins grew up behind the sheltered walls of the compound, where they were attended by a retinue of servants, cooks, and maids. Theirs was the life of the ruling aristocracy.
Adee, Mother's slight, soft-spoken, octogenarian grandmother, was the family's matriarch. With a taste for long black robes and soft linen headdresses, she was a spiritual healer of sorts who attracted a large following from the city. Her son, my grandfather, ran the day-to-day affairs of the household, and while deeply pious, he allowed a liberal atmosphere to flourish within the compound. The adults prayed five times a day, but the children were never forced to join them. Growing up, they developed different degrees of piety. Some, like my mother, were rigidly observant (her own mother came from a clerical background); others, especially the boys, rarely prayed, meekly avoiding Grandpa Baba's stern gaze during the five daily calls to prayer.
For a man of his position and generation, Grandpa was remarkably liberal, which inevitably led to some interesting contradictions. He had a deep sense of justice and fairness and did not play favorites among his five wives. He was pious yet never forced his children to pray. Religion was a matter between them and their God. In social and cultural matters he was open-minded, yet he strictly enforced pardah, which assured that nonblood male friends and guests never saw the faces of his womenfolk. He allowed his daughters to attend school, first fully covered and then, when the government made the burka voluntary, with their faces (although not their heads) uncovered. The daughters, out of respect as much as fear, would always hide their short, Western-style skirts and stockings by changing into baggy white cotton pants and linen headdresses before entering Grandpa's room. Once, in Kabul, he was persuaded to venture into the banquet hall where one of his younger daughters was having her wedding reception. Horrified by the sight of so many bare legs, including those of his own daughters, he barged out, cursing them all to hell.
In 1961, when Mother was thirteen, the first girls' school opened in Mazar-I Sharif. This was a bold act, considering that it had been the opening of a girls' school in Kabul during the 1920s that led to King Amanullah's downfall. Rabiah-I Balkhi Lycee for Girls presented a major dilemma to Grandpa, who as a respected member of society had to consider the social implications of exposing his sheltered daughters to the outside world. However, he valued education and, after consulting his two younger brothers, decided that all the girls in the family would go to school. A tutor was hired, and after a year of studying, they took entrance exams and enrolled in different grades. Mother was placed in the fifth grade, but by all accounts she was an unenthusiastic student drawn more to knitting sweaters than solving math problems. So by the time she was in the ninth grade, when Father's family proposed, she was happy to take his hand.
Father was my mother's second cousin, and his journey to northern Afghanistan had charted an improbable course. Unlike Mother, he was born in Islamabad, where his path to become a qadi, an Islamic judge, seemed a clear one. His father was a senior government administrator, his mother the daughter of a prominent mullah from the powerful Safi tribe. Although Grandpa Agha himself had chosen public service over a career in religion, he took pride in his clerical pedigree and wanted his three sons to pursue a religious path. While Grandpa served in remote provincial outposts, the family stayed behind in Islamabad, where Father studied first at the family mosque, then later at the local primary school. Along the way he developed a voracious appetite for reading. Years later he recounted how he spent a long winter devouring the bulky Thousand and One Nights, and any other classics he could get his hands on, by the glow of a kerosene lamp.
After sixth grade Father was sent to Kabul to attend the Darul Ulum-I Hanafi, Afghanistan's top state-run madrassah, or religious seminary, and a stepping stone to entering the College of Islamic Law at Kabul University. It was distinctly modern in amenities and curriculum, offering classes in both secular and traditional religious subjects.
The madrassah was originally developed during the eleventh century, a full two centuries before its European counterpart, as an institution of religious learning that trained students in Islamic law and jurisprudence. While European colleges would evolve into secular institutions of higher learning, the madrassah retained its religious mission. During the late nineteenth and early twentieth centuries, the madrassah's strictly religious curriculum and conservative intellectual outlook were called into question by a growing number of Islamic reformists. Recognizing the central role the scientific revolution and the Enlightenment played in the West's march to progress and prosperity, these modernist thinkers argued that only by embracing European sciences could the Islamic world hope to regain its ancient glory. The ensuing decades-long clash between the conservative religious establishment and the reformists produced little change in the madrassah curriculum, but it did lead Westernized governments such as Turkey and Persia to open modern secular schools.
In Afghanistan this clash led to the establishment of the country's first secular public high schools in the first and second decades of the twentieth century. Yet young King Amanullah's radical efforts to reshape Afghanistan in the image of Kemal Atatürk's Turkey backfired. Less than ten years into his reign, an alliance of conservative mullahs and southern tribesmen forced him into exile in 1929. Amanullah's successor, Nadir Khan, a reform-minded, pragmatic prince and former army general, recognized the limitations of his conservative society. While reopening the public schools, his government established new madrassahs where modern sciences were taught alongside traditional religious sciences, much like the madrassah my father attended.
Father's education was innovative, especially in its teaching of contemporary spoken Arabic. Young, sophisticated, and friendly Iraqi and Egyptian teachers introduced colloquial Arabic into a curriculum that had emphasized classical Arabic for hundreds of years. Classical Arabic grammar had developed on the basis of the Koran and pre-Islamic bedouin poetry, and its usefulness was limited to unraveling the messages of the Koran and the Hadith, or the sayings of Muhammad. Students learned to say, "Potipher's wife tore Joseph's shirt from behind," but could not share their enthusiasm for their mother's eggplant dish. The Arabic that Father learned in madrassah was, by contrast, a living, spoken language.
As much as Father loved to read, he was drawn even more to the sciences: the thrill generated by solving algebraic problems; the allure of the intricacies of human anatomy; the awe inspired by invisible atoms. This would inevitably lead to complications. While in the ninth grade, Father committed one of the most sacrilegious acts imaginable in a madrassah. Following instructions in his chemistry textbook, he distilled alcohol using simple household pots and pans. The successful experiment, which he secretly shared with more than a few classmates, deepened his passion for science and led him to drift away from the madrassah altogether. Kabul at the time was a charming, well-to-do city with tree-lined boulevards, tranquil neighborhoods, and thriving restaurants and teahouses frequented by the country's growing, largely Western educated, secular elite.
In Kabul, Father spent his weekends and short holiday breaks from school at the home of his uncle, who was the chief justice of the supreme court and a close friend of the madrassah's president. Uncle Insaf exhorted Father to excel in his religious studies, but Father was more interested in tutoring the justice's young, studious son in physics. It was an ideal arrangement, as Father didn't particularly fit in with Kabul's clean-shaven men who wore Western-style clothes and spoke with the refined accent of educated elites. He was torn between a desire to embrace Kabul's liberal culture and an awareness that he was forbidden by his father to do so. Feeling alienated, he would return to his dorm room every night and lie in bed, quietly imitating the Kabul accent he badly wanted to pick up, and painfully conscious he'd have to live with his facial hair for the rest of his life.
Then opportunity knocked: a science school recently founded by the University of Wyoming in Kabul was taking applications. Father took the placement test and scored ninety-nine out of a hundred points. He dropped out of the madrassah, despite his father's refusal to give his blessing, and enrolled at the American Technical School. There he spent the four happiest years of his life. He shaved off his beard, stopped praying, quickly learned English, and immersed himself in mechanical engineering. Although his friends playfully called him maulana, which means "supermullah," the title of a distinguished man of religious learning, he socialized at teahouses and befriended worldly university students.
After graduation he took a job as an engineer with the state-run Oil and Gas Exploration Company, spending the next several years working the fields near Sheberghan before winning a scholarship to study petroleum engineering in Soviet Armenia and Azerbaijan.
When Father returned to Afghanistan in 1966, he was thirty-three, well past the marriage age. It was time for him to settle down. At the urging of his parents, he agreed to an arranged marriage to his first cousin's daughter. Theirs was a grand wedding, paid for by Father's family. Payment for the ceremony was the only cost Grandpa Baba exacted. To him the custom of paying a bride price, which was common in northern Afghanistan, was an abomination; it was also un-Islamic. He expected, though, that the would-be groom would honor his family, so instead of pledging a large amount of cash and prime real estate, Father's family threw a weeklong party, complete with separate bands of male and female musicians—for male and female guests—to which hundreds of friends and relatives were invited. Father and Mother then moved to Sheberghan, bringing along several trunks and a young Uzbek servant named Girau.
In Sheberghan, they lived on the oil and gas company's campus, a sprawling development of offices and residential neighborhoods complete with green, manicured lawns, running water, electricity, and central heating—amenities unheard of in most of Afghanistan.
In many respects, however, Sheberghan was like any other small provincial capital: quiet, dusty, low-key, timeless. This was where Afghanistan's national ring road, built by the Americans and the Soviets in the 1950s and 1960s, ended before branching off west and north to the Amu Darya River. The main street was lined by handsome one- and two-story concrete homes, but for the most part Sheberghan consisted of flat-topped and domed mud huts and windy dirt roads that produced dust storms in the summer and turned into mud in the winter.
Things You Get for Free
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by Deborah Weisgall
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As I said, polymorphism is powerful and provides flexibility and dynamic behaviour to your code. In order to take use of Polymorphism, you can either use interface or abstract class in Java. Interface provides highest degree of abstraction. For example following code, which is based on interfaces, and an example of programming to interface than implementation principle, is flexible enough to work with any Map implementation in Java.
If you look closely, you will find that, most of the time we use methods from interface. For example, here we are using get() method from Map interface, you could definitely write following code in terms of HashMap or Hashtable, but then you switched to another implementation e.g. ConcurrentHashMap, you need to change your code. Here, we are using Map interface for getting Employee object from Cache, which can be any valid Map implementation, including HashMap, Hashtable, or ConcurrentHashMap. On similar line, you should use interface as Type of method arguments and as return type. This makes your code flexible enough to operate on any implementation.
If you are familiar of famous GOF design patterns than you know that most of the behavioural pattern use Polymorphism for dynamic behaviour, e.g. Decorator pattern, implements same interface as the object, which it decorates. If you don't use interface, it would be impossible to incorporate design patterns e.g. if your method accept concrete type, rather than abstract type, then you can not pass anything else to them. You not only lose flexibility but also runtime behaviour enrichment. Similarly, Composite pattern also uses same interface as object it contains, and this allows caller to deal with a normal object or composite object in same way, had they don't use interface, it wasn't possible. Proxy and Adapter design pattern also relies on higher level abstraction e.g. interface or abstract class, to provide added behaviour. In short, interface is not just a good coding practice, it also open path to incorporate other best practices in your code.
Testing is a big concern for any Project. Project Managers, Technical lead and developers will always prefer a code which can be unit tested easily in isolation with other moving parts. When we use interfaces in our code, our method start depending upon interfaces than implementation, which makes unit testing extremely easy. For example, a code which is using Database can not be tested in isolation, until database is available, but if same code is using interface to interact with database layer (DAO design pattern), you can always provide a dummy or mock object to mimic database calls. By using interface in your code, you get flexibility everywhere.
That's all on why you should use interface in Java. Though you can not define concrete methods, it's best way to introduce abstraction in your design. Real use of interface is to improve code quality by allowing modules to depend upon higher level of abstraction, which is less likely to change than lower level concrete classes, which is more likely to change. Use of interface also opens opportunities for using tried and tested Java design pattern and immensely helps in Unit testing as well. Most importantly, use of interface will give you different level of thinking and probably it's one step in mastering object oriented analysis and design.
Interfaces are needed where you expect volatility in your program, points at which you anticipate change, points where your design needs to bend.
Implementation is fragile in this sense: it breaks quite easily. This is why subclassing isn't always the best solution, just as long-winded methods that implement some complicated behavior all by themselves are generally a bad idea.
Interfaces are more flexible and can deal with a lot more stress on the design of your program than implementation.
By introducing interfaces into your program, you really introduce points of variation at which you can plug in different implementations for that interface. Interfaces' primary purpose is abstraction, decoupling the "what" from the "how".
Once you get used to it, you'll find it's a great (actually essential) way to work.
(assuming IBox has a close() method) even though the actual class of myBox changes depending on which box you're at in the iteration.
First and formost reason of using Interface is working with abstraction rather than implementation. When you work with generic abstraction, you have a chance to swap implementation which gives flexibility to your program. In the long run, use of interface improves flexibility, maintainability, and performance of Java application? how come performance? because it allows you to develop new high performance implementation and swap them without chaning the client code. In short, you must code with interface e.g. use interface as type of variable, use interface in method parameter, use interface while extending or impelementing e.g. extend from Map not from HashMap.
Hey man I've a doubt. Why do we need an interface at all? Why can't we directly define the chew function in the reptile class and not in bird class?


20. Jesus mother said to Him, "They have no more wine" (John 2:3).
How quickly do we turn to God in our search for help or answers? One wonders at the expectations of Mary, since there are no previously recorded miracles in Jesus' life. What did she think He might do? Still, the things she has treasured in her heart surely were longing for expression, so her quest isn't a complete surprise. Do we look to Christ for such simple things? Do we think the Divine nature will integrate with our common moments? Clearly Mary saw this moment as possessing the potential for revelation. Do we see our simple moments as similar opportunities?