Department Physiology and Pathology of Ion Transport (Thomas J. Jentsch)

RESEARCH SUMMARIES

Ion transport processes play pivotal roles in neuronal excitability, signal transduction, transport of salt, water, and other substances across epithelia, and the homeostasis of extracellular, cytosolic, and vesicular compartments. Accordingly, mutations in ion channels or transporters underlie several, very diverse human diseases.

We use highly interdisciplinary approaches to mechanistically understand ion transport at all levels. Our investigations include biophysical structure-function analysis of mutated channels, address key cell biological aspects like endocytosis and lysosomal function, and elucidate the physiological and systemic role of particular transport proteins with extensive use of sophisticated genetic mouse models. We have identified ion channel mutations in several human diseases. These disorders include epilepsy and neurodegeneration, deafness, kidney stones, urinary protein loss, hypertension, and thick bones (osteopetrosis), among others.

We investigate the functions of CLC Cl- channels and transporters, KCNQ K+ channels, KCC K-Cl-cotransporters, and Anoctamin Ca2+-activated Cl- channels. Our recent work has revealed   the long-sought molecular identity of VRAC, the volume-regulated anion channel that is ubiquitously expressed in mammalian cells. VRAC not only plays a central role in cell volume regulation, but also in amino-acid release and is believed to be important for cell proliferation, migration, apoptosis, and to be involved in several pathological conditions. Having finally identified VRAC, we have begun several projects concerning this important channel. The following gives short summaries of our past results and recent or ongoing projects.

CLC Cl- channels and transporters

We discovered the CLC gene family in 1990 by expression cloning of the voltage-gated Cl- channel from the electric organ of the marine ray Torpedo [1]. This channel, which we baptized ClC-0, is the founding member of the CLC gene family which is present from bacteria to men. In humans, it comprises 9 members (Figure 1) (for review, see [2]). Originally thought to only represent plasma membrane Cl- channels, many of these proteins rather function as electrogenic Cl-/H+-exchangers in intracellular membranes. Mutations of CLC genes underlie several human genetic diseases. We have shown that some CLC proteins associate with other, structurally unrelated proteins, mutations in which cause pathologies that overlap with those observed with the loss of their respective CLC partners.

Figure 1. The CLC gene family of Cl- channels and Cl-/H+-exchangers. Associated  structurally unrelated β-subunits include the cell adhesion molecule GlialCAM (mutations in which underlie a distinct form of leukodystrophy) for ClC-2, the 2-membrane span membrane protein barttin (mutations in which lead to Bartter syndrome with deafness) for both ClC-K isoforms, and for ClC-7 Ostm1, with disruption of either gene leading to osteopetrosis associated with neurodegeneration.

Important new insights were obtained from our disruption of CLC genes in mice. For instance, the disruption of the chloride transporter ClC-7 unexpectedly led to osteopetrosis [3], a hypercalcification of bone. This phenotype is due to a dysfunction of osteoclasts, the cells that are responsible for bone degradation. ClC-7 currents may balance the electrogenic transport of the H+-ATPase that acidifies the resorption lacuna (Figure 2).

Figure 2. Role of ClC-7 in osteopetrosis. a, X-ray of bones from wild-type (WT) and ClC-7 KO mice reveals hypercalci­fication in the KO. b, model for the acidification of the osteoclast resorption lacuna.

Motivated by these findings, we identified mutations in either the ClC-7 chloride transporter [3], or in the a3 subunit of the H+-ATPase [4], in human patients with severe juvenile osteopetrosis. ClC-7 is normally present in a lysosomal compartment, but is inserted into the plasma membrane of osteoclasts. Similarly, our results show that ClC-3 through ClC-6 reside normally in membranes of intracellular compartments, where they may contribute to their acidification by electrical shunting of the proton ATPase. ClC-5, a Cl-/H+ exchanger mutated in the kidney stone disorder Dent’s disease [5], is present in renal endosomes [6]. Our ClC-5 knock-out mouse model [7] revealed that an impaired endosomal acidification led to a broad defect in proximal tubular endocytosis. This entails secondary changes in calciotropic hormones, eventually resulting in the hyperphosphaturia and hypercalciuria (and kidney stones) in Dent’s disease. The related ClC-3 putative Cl-/H+ exchanger is also present in endosomes, as well as in synaptic vesicles [8]. As the uptake of neurotransmitters into synaptic vesicles is coupled to the proton gradient, this may have interesting consequences for synaptic transmission. Surprisingly, the knock-out of ClC-3 led to nearly complete degeneration of the hippocampus [8].

In the classical model of vesicular acidification (Figure 3a), the electrical current of the vesicular H+-ATPase is neutralized by Cl- influx through a Cl- channel.  The discovery that vesicular CLCs are 2Cl-/H+-exchangers rather than Cl- channels [9, 10] therefore came as a surprise because a role in acidification rather seemed counterintuitive.

Figure 3. Back to classics. We generated ClC-5 and ClC-7 knock-in mice in which we converted the WT 2Cl-/H+-exchangers ClC-5 and ClC-7 (b) with point mutations into mere Cl- conductances (c) to conform to the classical model (a) of vesicular acidification.

To elucidate whether vesicular CLCs just serve to neutralize proton pump currents, we converted ClC-5 and ClC-7 in mice to pure Cl- conductances [11, 12]. Any phenotype apparent in those mice cannot be ascribed to a defect in vesicular acidification. Surprisingly, these mice displayed grossly the same phenotype as the corresponding KO mice, suggesting an important role of vesicular Cl- accumulation. Another recent ClC-7 knock-in mouse [13] revealed that not only ion transport activity, but also (so far unknown) protein-protein interactions account for ClC-7 functions. Several current projects of our lab focus on the exciting roles of vesicular CLCs in basic cellular processes and pathological states.

ClC-2 is a widely expressed plasma membrane Cl- channel that is slowly activated by inside-negative voltage or cell swelling [14, 15]. We showed previously that disruption of ClC-2 in mice leads to testicular and retinal degeneration [16], as well as leukodystrophy [17]. Recently van der Knaap and colleagues showed that human ClC-2 mutations also lead to leukodystrophy, a disease associated with vacuolization of the white matter (glia) of the central nervous system.  Together with Raúl Estévez we have recently shown that ClC-2 associates with GlialCAM, an Ig-like cell adhesion cell surface molecule, and that this interaction profoundly changes ClC-2 gating [18]. Importantly, GlialCAM mutations also lead to human leukodystrophy, as do mutations in MLC1, a protein interaction partner of GlialCAM that displays several transmembrane domains. We recently generated GlialCAM mouse models and compared their CNS pathology to those of ClC-2 and MLC1 KO mice [19]. Unexpectedly, the localization, abundance and biophysical properties of ClC-2 depended on both GlialCAM and MLC1, suggesting changes in ClC-2 as a common pathogenic factor in the respective diseases. Several current projects focus on ClC-2 and its role in the CNS.

Volume-stimulated organic osmolyte / anion channel VSOAC/VRAC

Cells need to regulate their volume in face of osmotic stress and during cell growth, migration, and apoptosis. A key player in regulatory volume decrease is the volume-regulated anion channel VRAC (also known as VSOR or VSOAC) that opens upon cell swelling. Its opening leads to a passive efflux of chloride that is electrically balanced by K+-efflux through constitutively open K+ channels. Cell swelling also leads to an efflux of organic osmolytes like taurine or glutamate, but it was controversial whether this occurs through the same channel. As water transport across cellular membranes is driven by osmotic gradients, opening of VRAC/VSOAC leads to water efflux and to cell shrinkage (Figure 4).

Whereas the biophysical footprint of VRAC has been known since the late 1980s, and while the channel has been described and analyzed in hundreds of publications, attempts to identify the underlying molecule(s) have failed repeatedly. In collaboration with the in-house FMP screening facility, we recently used a genome-wide RNA interference screen to identify LRRC8A as an essential component of VRAC [20]. LRRC8A displays four transmembrane domains and a large cytoplasmic tail containing many leucine-rich repeats (LRRs). It has four close homologs (LRRC8B-E) and recent bioinformatic analysis had shown that LRRC8 proteins are distantly related to pannexins that form hexameric plasma membrane channels. Co-immunoprecipitation and intracellular trafficking experiments showed that LRRC8A can form heteromers with these other members. Using the novel CISPR-Cas genomic editing tool, we disrupted all five LRRC8 genes in cells singly and in several combinations (including a cell line with disruption of all five LRRC8 genes) and reconstituted selected LRRC8 isoforms by transfection [20]. Electrophysiological analysis revealed that only LRRC8A is essential for VRAC function, but that it needs at least one other LRRC8 isoform (LRRC8B-E) to yield currents. Different combinations of LRRC8A with other isoforms (e.g. LRRC8C or LRRC8E) yielded VRAC currents that differed in their inactivation kinetics, proving that LRRC8 proteins are integral parts of the channel and not just involved in its activation. As LRRC8 isoforms display differential tissue distribution our results also explain the differences in inactivation kinetics of VRAC currents in different tissues that had been enigmatic.

Importantly, we also showed that the efflux of the sulfoamino-acid taurine, an important cellular osmolyte, also depends on LRRC8 heteromers, showing that VRAC is indeed identical to VSOAC [20]. We suspect that the same channel conducts a number of other organic substances, several of which may be involved in signal transduction (e.g. taurine is known to act on GABA receptors).  Genetic LRRC8 mouse models will be essential to elucidate the various postulated and novel cellular and organismal functions of this newly identified channel. The biophysical and physiological analysis of VRAC/VSOAC has become a major focus of our lab.

Figure 4. Schematic diagram of VRAC function. VRAC is closed under resting conditions (top left) and opens after osmotic swelling. The resulting efflux of chloride and organic osmolytes decreases cellular osmolarity, resulting in water efflux and regulatory volume decrease.

TMEM16 / Anoctamin Ca2+-activated Cl- channels

TMEM16A (Anoctamin 1) was identified as Ca2+-activated Cl- channel by three groups in 2008. It belongs to a gene family with ten members, but it is currently unclear whether all of them display Cl- channel function (some of them work as lipid scramblases). In our studies we have focused on TMEM16B (Ano2), which in contrast to TMEM16A (Ano1) shows a very restricted expression with high expression levels in the nose and in the retina. By generating and analyzing Ano2 knock-out mice we demonstrated [21] that Ano2 is the long-sought Ca2+-activated Cl- channel of olfactory sensory neurons which was thought to amplify olfactory responses by a factor of ten. Surprisingly, however, the transepithelial electrical response of the main olfactory epithelium to odorants was almost normal, and no effect of the loss of Ano2 on olfaction could be found in behavioral olfactometry experiments. We thus conclude that Ca2+-activated Cl- channels are dispensable for olfaction [21].

Whereas Ano2 is the only Ca2+-activated Cl- channel in sensory neurons of the main olfactory epithelium, the vomeronasal organ (VNO) of the mouse, which is specialized in detecting socially important moieties such as pheromones, expresses both Ano1 and Ano2. Current projects in the lab concern the signal transduction in the VNO and other physiological roles of TMEM16 / Anoctamin members.

KCC K+/Cl- cotransporters

Over the past ten years, we have also worked on electroneutral KCC K-Cl cotransporters that stoichiometrically couple the movement of chloride to that of potassium. This coupling leads generally to a lowering of the cytoplasmic Cl- concentration.  In neurons, this concentration determines whether the response to the neurotransmitters GABA and glycine is inhibitory (as in most adult neurons) or excitatory (as early in development). ClC-2 is thought to play a role in this regulation, but the disruption of this Cl- channel led to male infertility, blindness and leukodystrophy rather than to CNS hyperexcitability. By contrast, the disruption of the neuronal K-Cl cotransporter KCC2 led to perinatal death due to the inability to breathe and to a spastic phenotype [22]. This was indeed due to an increase in intracellular chloride in motoneurons. The knock-out of KCC4 led to a rapid hearing loss that was associated with renal tubular acidosis [23], whereas the disruption of KCC3 led to a degeneration of the nervous system, deafness, and hypertension [24, 25]. Finally, we have shown that KCC1 and KCC3 co-operate in regulating the volume of red blood cells [26]. Genetic elimination of both transporters partially alleviates the symptoms of sickle-cell anemia.

More recently, we have used ‘floxed’ Kcc2 mice to disrupt Kcc2 only in a subset of specific neurons like cerebellar granule and Purkinje cells [27]. In both cell types, KCC2 ablation significantly increased the cytoplasmic Cl- concentration. It nearly abolished GABA-ergic hyperpolarization of Purkinje cells and increased the excitability of granule cells (GCs) through depolarization. Ablation of Kcc2 from GCs impaired consolidation of long-term phase learning of the vestibulo-ocular reflex, revealing a previously unknown role of GC excitability in consolidation of phase learning [27]. We are currently studying mice carrying specific Kcc2 deletions in other classes of neurons.

KCNQ (Kv7) K+ channels

We have previously identified KCNQ2,3,4 and 5 as novel members of the voltage-gated K+ channel superfamily [28, 29, 30] and have shown that mutations in KCNQ2 and KCNQ3, which can form heteromeric channels [31], may lead to neonatal epilepsy [28]. KCNQ2, KCNQ3, and KCNQ5 mediate neuronal M-currents, a highly regulated potassium current that is already active at resting potentials and that sensitively regulates neuronal excitability. We  also showed that KCNQ4 is mutated in a form of dominant deafness [29]. It is expressed in sensory hair cells of the inner ear [32]. We generated mouse models for KCNQ4 to elucidate its role in human deafness [33]. Some KCNQ K+ channels can associate with ß-subunits of the KCNE family. We showed that KCNE3 abolishes the gating of KCNQ1 channels [34] and, using a KCNE3 KO mouse, demonstrated that KCNQ1/KCNE3 heteromers are important for Cl- secretion in the intestine [35].

More recently we investigated the roles of KCNQ4 and KCNQ5 in the vestibular organ using genetic mouse models [36]. Although both channel proteins accumulate at the calyx synapse of vestibular hair cells, both channels are located in the postsynaptic membrane, in contrast to the presynaptic localization of KCNQ4 in cochlear outer hair cells [32]. The importance of KCNQ channels in vestibular function was demonstrated by abnormal vestibule-ocular reflexes.

In addition to the cochlea and the vestibular organ, KCNQ4 is also expressed in selected nuclei of the brainstem, including the auditory pathway and trigeminal ganglia [32]. It is also expressed in a small fraction of large diameter dorsal root ganglion neurons [37]. We showed that it is specifically expressed in rapidly adapting mechanosensors in the skin. Disruption of KCNQ4 severely impairs the frequency tuning of these receptors in mice, as well as in deaf patients carrying KCNQ4 mutations [37]. We are currently investigating the peripheral and central roles of several KCNQ channels using genetic mouse models.

1.  Jentsch TJ, Steinmeyer K, Schwarz G (1990) Primary structure of Torpedo marmorata chloride channel isolated by expression cloning in Xenopus oocytes. Nature 348: 510-514.

2.  Stauber T, Weinert S, Jentsch TJ (2012) Cell biology and physiology of CLC chloride channels and transporters. Compr Physiol 2: 1701-1744.

3.  Kornak U, Kasper D, Bösl MR, Kaiser E, Schweizer M, Schulz A, Friedrich W, Delling G, Jentsch TJ (2001) Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell 104: 205-215.

4.  Kornak U, Schulz A, Friedrich W, Uhlhaas S, Kremens B, Voit T, Hasan C, Bode U, Jentsch TJ, Kubisch C (2000) Mutations in the a3 subunit of the vacuolar H+-ATPase cause infantile malignant osteopetrosis. Hum Mol Genet 9: 2059-2063.

5.  Lloyd SE, Pearce SH, Fisher SE, Steinmeyer K, Schwappach B, Scheinman SJ, Harding B, Bolino A, Devoto M, Goodyer P, Rigden SP, Wrong O, Jentsch TJ, Craig IW, Thakker RV (1996) A common molecular basis for three inherited kidney stone diseases. Nature 379: 445-449.

6.  Günther W, Luchow A, Cluzeaud F, Vandewalle A, Jentsch TJ (1998) ClC-5, the chloride channel mutated in Dent's disease, colocalizes with the proton pump in endocytotically active kidney cells. Proc Natl Acad Sci U S A 95: 8075-8080.

7.  Piwon N, Günther W, Schwake M, Bösl MR, Jentsch TJ (2000) ClC-5 Cl--channel disruption impairs endocytosis in a mouse model for Dent's disease. Nature 408: 369-373.

8.  Stobrawa SM, Breiderhoff T, Takamori S, Engel D, Schweizer M, Zdebik AA, Bösl MR, Ruether K, Jahn H, Draguhn A, Jahn R, Jentsch TJ (2001) Disruption of ClC-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus. Neuron 29: 185-196.

9.  Scheel O, Zdebik A, Lourdel S, Jentsch TJ (2005) Voltage-dependent electrogenic chloride proton exchange by endosomal CLC proteins. Nature 436: 424-427.

10. Leisle L, Ludwig CF, Wagner FA, Jentsch TJ, Stauber T (2011) ClC-7 is a slowly voltage-gated 2Cl-/1H+-exchanger and requires Ostm1 for transport activity. EMBO J 30: 2140-2152.

11. Novarino G, Weinert S, Rickheit G, Jentsch TJ (2010) Endosomal chloride-proton exchange rather than chloride conductance is crucial for renal endocytosis. Science 328: 1398-1401.

12. Weinert S, Jabs S, Supanchart C, Schweizer M, Gimber N, Richter M, Rademann J, Stauber T, Kornak U, Jentsch TJ (2010) Lysosomal pathology and osteopetrosis upon loss of H+-driven lysosomal Cl- accumulation Science 328: 1401-1403.

13. Weinert S, Jabs S, Hohensee S, Chan WL, Kornak U, Jentsch TJ (2014) Transport activity and presence of ClC-7/Ostm1 complex account for different cellular functions. EMBO Rep 15: 784-781.

14. Gründer S, Thiemann A, Pusch M, Jentsch TJ (1992) Regions involved in the opening of CIC-2 chloride channel by voltage and cell volume. Nature 360: 759-762.

15. Thiemann A, Gründer S, Pusch M, Jentsch TJ (1992) A chloride channel widely expressed in epithelial and non-epithelial cells. Nature 356: 57-60.

16. Bösl MR, Stein V, Hübner C, Zdebik AA, Jordt SE, Mukhophadhyay AK, Davidoff MS, Holstein AF, Jentsch TJ (2001) Male germ cells and photoreceptors, both depending on close cell-cell interactions, degenerate upon ClC-2 Cl--channel disruption. EMBO J 20: 1289-1299.

17. Blanz J, Schweizer M, Auberson M, Maier H, Muenscher A, Hübner CA, Jentsch TJ (2007) Leukoencephalopathy upon disruption of the chloride channel ClC-2. J Neurosci 27: 6581-6589.

18. Jeworutzki E, López-Hernández T, Capdevila-Nortes X, Sirisi S, Bengtsson L, Montolio M, Zifarelli G, Arnedo T, Müller CS, Schulte U, Nunes V, Martínez A, Jentsch TJ, Gasull X, Pusch M, Estévez R (2012) GlialCAM, a protein defective in a leukodystrophy, serves as a ClC-2 Cl- channel auxiliary subunit. Neuron 73: 951-961.

19. Hoegg-Beiler MB, Sirisi S, Orozco IJ, Ferrer I, Hohensee S, Auberson M, Godde K, Vilches C, de Heredia ML, Nunes V, Estevez R, Jentsch TJ (2014) Disrupting MLC1 and GlialCAM and ClC-2 interactions in leukodystrophy entails glial chloride channel dysfunction. Nat Commun 5: 3475.

20. Voss FK, Ullrich F, Münch J, Lazarow K, Lutter D, Mah N, Andrade-Navarro MA, von Kries JP, Stauber T, Jentsch TJ (2014) Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC. Science 344: 634-638.

21. Billig GM, Pál B, Fidzinski P, Jentsch TJ (2011) Ca2+-activated Cl- currents are dispensable for olfaction. Nat Neurosci 14: 763-769.

22. Hübner CA, Stein V, Hermans-Borgmeyer I, Meyer T, Ballanyi K, Jentsch TJ (2001) Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition. Neuron 30: 515-524.

23. Boettger T, Hübner CA, Maier H, Rust MB, Beck FX, Jentsch TJ (2002) Deafness and renal tubular acidosis in mice lacking the K-Cl co-transporter Kcc4. Nature 416: 874-878.

24. Boettger T, Rust MB, Maier H, Seidenbecher T, Schweizer M, Keating DJ, Faulhaber J, Ehmke H, Pfeffer C, Scheel O, Lemcke B, Horst J, Leuwer R, Pape HC, Volkl H, Hübner CA, Jentsch TJ (2003) Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold. EMBO J 22: 5422-5434.

25. Rust MB, Faulhaber J, Budack MK, Pfeffer C, Maritzen T, Didie M, Beck FX, Boettger T, Schubert R, Ehmke H, Jentsch TJ, Hübner CA (2006) Neurogenic mechanisms contribute to hypertension in mice with disruption of the K-Cl cotransporter KCC3. Circ Res 98: 549-556.

26. Rust MB, Alper SL, Rudhard Y, Shmukler BE, Vicente R, Brugnara C, Trudel M, Jentsch TJ, Hübner CA (2007) Disruption of erythroid K-Cl cotransporters alters erythrocyte volume and partially rescues erythrocyte dehydration in SAD mice. J Clin Invest 117: 1708-1717.

27. Seja P, Schonewille M, Spitzmaul G, Badura A, Klein I, Rudhard Y, Wisden W, Hübner CA, De Zeeuw CI, Jentsch TJ (2012) Raising cytosolic Cl- in cerebellar granule cells affects their excitability and vestibulo-ocular learning. Embo J 31: 1217-1230.

28. Biervert C, Schroeder BC, Kubisch C, Berkovic SF, Propping P, Jentsch TJ, Steinlein OK (1998) A potassium channel mutation in neonatal human epilepsy. Science 279: 403-406.

29. Kubisch C, Schroeder BC, Friedrich T, Lütjohann B, El-Amraoui A, Marlin S, Petit C, Jentsch TJ (1999) KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell 96: 437-446.

30. Schroeder BC, Hechenberger M, Weinreich F, Kubisch C, Jentsch TJ (2000) KCNQ5, a novel potassium channel broadly expressed in brain, mediates M-type currents. J Biol Chem 275: 24089-24095.

31. Schroeder BC, Kubisch C, Stein V, Jentsch TJ (1998) Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature 396: 687-690.

32. Kharkovets T, Hardelin JP, Safieddine S, Schweizer M, El-Amraoui A, Petit C, Jentsch TJ (2000) KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway. Proc Natl Acad Sci U S A 97: 4333-4338.

33. Kharkovets T, Dedek K, Maier H, Schweizer M, Khimich D, Nouvian R, Vardanyan V, Leuwer R, Moser T, Jentsch TJ (2006) Mice with altered KCNQ4 K+ channels implicate sensory outer hair cells in human progressive deafness. EMBO J 25: 642-652.

34. Schroeder BC, Waldegger S, Fehr S, Bleich M, Warth R, Greger R, Jentsch TJ (2000) A constitutively open potassium channel formed by KCNQ1 and KCNE3. Nature 403: 196-199.

35. Preston P, Wartosch L, Gunzel D, Fromm M, Kongsuphol P, Ousingsawat J, Kunzelmann K, Barhanin J, Warth R, Jentsch TJ (2010) Disruption of the K+ channel beta-subunit KCNE3 reveals an important role in intestinal and tracheal Cl- transport. J Biol Chem 285: 7165-7175.

36. Spitzmaul G, Tolosa L, Winkelman BH, Heidenreich M, Frens MA, Chabbert C, de Zeeuw CI, Jentsch TJ (2013) Vestibular role of KCNQ4 and KCNQ5 K+ channels revealed by mouse models. J Biol Chem 288: 9334-9344.

37. Heidenreich M, Lechner SG, Vardanyan V, Wetzel C, Cremers CW, De Leenheer EM, Aránguez G, Moreno-Pelayo MA, Jentsch TJ, Lewin GR (2012) KCNQ4 K+ channels tune mechanoreceptors for normal touch sensation in mouse and man. Nat Neurosci 15: 138-145.

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