In animals, stored fat provides a rich source of energy to sustain basal metabolic processes to survive periods of nutrient scarcity, and to support reproduction (Heier and Kühnlein, 2018; Heier et al., 2021; Walther and Farese, 2012). The main form of stored fat is triglyceride, which is deposited within specialized organelles called lipid droplets (Kühnlein, 2012; Murphy, 2001; Thiele and Spandl, 2008). Lipid droplets are found in many cell types throughout the body, but the main organ responsible for triglyceride storage is the adipose tissue (Murphy, 2001). The amount of triglyceride in the adipose tissue is regulated by many factors; however, one important factor that influences an individual’s whole-body fat level is whether the animal is female or male (Karastergiou et al., 2012; Power and Schulkin, 2008; Sieber and Spradling, 2015; Wat et al., 2020). Typically, females store more fat than males. In mammals, females store approximately 10% more body fat than males (Jackson et al., 2002; Karastergiou et al., 2012; Womersley and Durnin, 1977). Female insects, on the other hand, can store up to four times more fat than males of the same species (Lease and Wolf, 2011) and break down fat more slowly than males when nutrients are scarce (Wat et al., 2020). These male-female differences in fat metabolism play a key role in supporting successful reproduction in each sex: females with reduced fat storage often show lower fecundity (Buszczak et al., 2002; Sieber and Spradling, 2015) whereas males with excess fat storage generally show decreased fertility (Grönke et al., 2005; Wat et al., 2020). Given that fat storage also influences diverse phenotypes such as immunity and lifespan (DiAngelo and Birnbaum, 2009; Gáliková and Klepsatel, 2018; Johnson and Stolzing, 2019; Kamareddine et al., 2018; Liao et al., 2021; Roth et al., 2018; Suzawa et al., 2019), the sex-specific regulation of fat storage has implications for several life-history traits. Yet, the genetic and physiological mechanisms that link biological sex with fat storage remain incompletely understood in many animals.

Clues into potential mechanisms underlying the sex difference in fat storage have emerged from studies on the regulation of triglyceride metabolism in Drosophila. While many pathways impact whole-body triglyceride levels (Ballard et al., 2010; Bjedov et al., 2010; Broughton et al., 2005; Choi et al., 2015; DiAngelo and Birnbaum, 2009; Francis et al., 2010; Ghosh and O’Connor, 2014; Grönke et al., 2010; Heier and Kühnlein, 2018; Heier et al., 2021; Hentze et al., 2015; Kamareddine et al., 2018; Kang et al., 2017; Kubrak et al., 2020; Lee et al., 2019; Lehmann, 2018; Luong et al., 2006; Rajan and Perrimon, 2012; Roth et al., 2018; Scopelliti et al., 2019; Sieber and Spradling, 2015; Song et al., 2014; Song et al., 2017; Suzawa et al., 2019; Teleman et al., 2005; Texada et al., 2019), the Adipokinetic hormone (Akh; FBgn0004552) pathway plays a central role in regulating whole-body fat storage and breakdown (Heier and Kühnlein, 2018; Heier et al., 2021; Lehmann, 2018). Akh is synthesized as a preprohormone in the Akh-producing cells (APCs), and is subsequently cleaved by proprotein convertases to produce active Akh (Lee and Park, 2004; Noyes et al., 1995; Predel et al., 2004; Wegener et al., 2006). When the APCs are activated by stimuli such as peptide hormones or neurons that make physical connections with the APCs (Kubrak et al., 2020; Oh et al., 2019; Scopelliti et al., 2019; Zhao and Karpac, 2017), Akh is released into the hemolymph (Braco et al., 2012).

Circulating Akh then interacts with a G-protein coupled receptor called the Akh receptor (AkhR, FBgn0025595), where Akh binding to AkhR on target tissues such as the fat body increases intracellular cyclic adenosine monophosphate (cAMP) levels. High levels of cAMP activate protein kinase A (PKA; FBgg0000242) (Gäde and Auerswald, 2003; Park et al., 2002; Staubli et al., 2002), which phosphorylates several downstream metabolic effectors to promote fat breakdown. For example, in insects, active PKA promotes fat breakdown via phosphorylation and activation of Lipid storage droplet-1 (Lsd-1; FBgn0039114) (Arrese et al., 2008; Bickel et al., 2009; Gäde and Auerswald, 2003; Patel et al., 2005). In mammals, fat breakdown is mediated by similar PKA-dependent phosphorylation of Perilipin 1, the mammalian homolog of Lsd-1, and by PKA-dependent phosphorylation and recruitment of lipases, such as Hormone-sensitive lipase (Hsl), to lipid droplets to promote fat mobilization (Sztalryd and Brasaemle, 2017). Given that these genes are highly conserved between mammals and flies (Kühnlein, 2012), similar PKA-dependent mechanisms likely explain triglyceride mobilization from lipid droplets. Thus, high levels of Akh pathway activity limit fat storage whereas low levels of Akh signaling promote fat storage. While Akh-mediated triglyceride breakdown plays a vital role in releasing stored energy during times of nutrient scarcity to promote survival (Mochanová et al., 2018), the Akh pathway limits fat storage even in contexts when nutrients are plentiful. Indeed, loss of Akh or AkhR augments fat storage in males under normal physiological conditions (Bharucha et al., 2008; Gáliková et al., 2015; Grönke et al., 2007), highlighting the critical role of this pathway in regulating whole-body triglyceride levels.

Additional clues into potential mechanisms underlying the sex difference in fat storage come from studies on metabolic genes. For example, flies carrying loss-of-function mutations in genes involved in triglyceride synthesis and storage, such as midway (mdy; FBgn0004797), Lipin (Lpin; FBgn0263593), Lipid storage droplet-2 (Lsd-2; FBgn0030608), and Seipin (Seipin; FBgn0040336) show reduced whole-body triglyceride levels (Buszczak et al., 2002; Grönke et al., 2003; Teixeira et al., 2003; Tian et al., 2011; Ugrankar et al., 2011; Wang et al., 2016). Whole-body deficiency for genes that regulate triglyceride breakdown, on the other hand, generally have higher whole-body fat levels. This is best illustrated by elevated whole-body triglyceride levels found in flies lacking brummer (bmm; FBgn0036449) or Hsl (FBgn0034491), both of which encode lipases (Bi et al., 2012; Grönke et al., 2005). While these studies demonstrate the strength of Drosophila as a model in revealing conserved mechanisms that contribute to whole-body fat storage (Recazens et al., 2021; Schreiber et al., 2019; Walther and Farese, 2012), studies on Drosophila fat metabolism often use single- or mixed-sex groups of flies (Bednářová et al., 2018; Gáliková et al., 2015; Grönke et al., 2007; Hughson et al., 2021; Isabel et al., 2005; Lee and Park, 2004; Scopelliti et al., 2019). As a result, less is known about how these metabolic genes and pathways contribute to the sex difference in fat storage.

Recent studies have begun to fill this knowledge gap by studying fat metabolism in both sexes. In one study, higher circulating levels of steroid hormone ecdysone in mated females were found to promote increased whole-body fat storage (Sieber and Spradling, 2015). Another study showed that elevated levels of bmm mRNA in male flies restricted triglyceride storage to limit whole-body fat storage (Wat et al., 2020). Yet, neither ecdysone signaling nor bmm fully explain known male-female differences in whole-body fat metabolism (Sieber and Spradling, 2015; Wat et al., 2020). This suggests additional metabolic genes and pathways must contribute to sex differences in fat storage and breakdown (Wat et al., 2020). Indeed, genome-wide association studies in Drosophila demonstrate sex-biased effects on fat storage for many genetic loci (Nelson et al., 2016; Watanabe and Riddle, 2021). As evidence of sex-specific mechanisms underlying whole-body fat storage continues to mount, several reports have also identified male-female differences in phenotypes linked with fat metabolism. For example, sex differences have been reported in energy physiology, metabolic rate, food intake, food preference, circadian rhythm, sleep, immune response, starvation resistance, and lifespan (Andretic and Shaw, 2005; Austad and Fischer, 2016; Belmonte et al., 2019; Chandegra et al., 2017; Helfrich-Förster, 2000; Huber et al., 2004; Hudry et al., 2019; Millington et al., 2021; Park et al., 2018; Reddiex et al., 2013; Regan et al., 2016; Sieber and Spradling, 2015; Videlier et al., 2019; Wat et al., 2020). More work is therefore needed to understand the genetic and physiological mechanisms underlying the male-female differences in fat metabolism, and to identify the impact of this sex-specific regulation on key life-history traits. Further, it will be critical to elucidate how these mechanisms are linked with upstream factors that determine sex.

In Drosophila, sexual development is determined by the number of X chromosomes (Salz and Erickson, 2010). In females, the presence of two X chromosomes triggers the production of a functional splicing factor called Sex-lethal (Sxl; FBgn0264270) (Bell et al., 1988; Bridges, 1921; Cline, 1978). Sxl’s most well-known downstream target is transformer (tra; FBgn0003741), where Sxl-dependent splicing of tra pre-mRNA allows the production of a functional Tra protein (Belote et al., 1989; Boggs et al., 1987; Inoue et al., 1990; Sosnowski et al., 1989). In males, which have only one X chromosome, no functional Sxl or Tra proteins are made (Cline and Meyer, 1996; Salz and Erickson, 2010). Over several decades, a large body of evidence has accumulated showing that Sxl and Tra direct most aspects of female sexual identity, including effects on abdominal pigmentation, egg-laying, neural circuits, and behavior (Anand et al., 2001; Baker et al., 2001; Billeter et al., 2006; Brown and King, 1961; Burtis and Baker, 1989; Camara et al., 2008; Christiansen et al., 2002; Cline, 1978; Cline and Meyer, 1996; Clough et al., 2014; Dauwalder, 2011; Demir and Dickson, 2005; Goodwin et al., 2000; Hall, 1994; Heinrichs et al., 1998; Hoshijima et al., 1991; Inoue et al., 1992; Ito et al., 1996; Nagoshi et al., 1988; Neville et al., 2014; Nojima et al., 2014; Pavlou et al., 2016; von Philipsborn et al., 2014; Pomatto et al., 2017; Rezával et al., 2014; Rezával et al., 2016; Rideout et al., 2007; Rideout et al., 2010; Ryner et al., 1996; Sturtevant, 1945). More recently, studies have extended our knowledge of how Sxl and Tra regulate additional aspects of development and physiology such as body size and intestinal stem cell proliferation (Ahmed et al., 2020; Hudry et al., 2016; Millington and Rideout, 2018; Millington et al., 2021; Regan et al., 2016; Rideout et al., 2015; Sawala and Gould, 2017). Yet, the effects of sex determination genes on whole-body fat metabolism remain unknown, indicating a need for more knowledge of how factors that determine sexual identity influence this important aspect of physiology.

Here, we reveal a role for sex determination gene tra in regulating whole-body triglyceride storage. In females, Tra expression promotes a higher level of whole-body fat storage, whereas lack of a functional Tra protein in males leads to lower fat storage. Interestingly, neurons were the anatomical focus of tra’s effects on fat storage, where we show that ectopic Tra expression in male APCs was sufficient to augment whole-body triglyceride levels. Our analysis of Akh pathway regulation in both sexes revealed increased Akh/AkhR mRNA levels, APC activity, and Akh pathway activity in males. Our findings indicate that this overall male bias in the Akh pathway contributes to the sex difference in whole-body triglyceride levels by restricting fat storage in males. Importantly, we show that the presence of Tra influences Akh pathway activity, and that Akh lies genetically downstream of Tra in regulating whole-body fat storage. These results provide new insight into the mechanisms by which upstream determinants of sexual identity, such as tra, influence the sex difference in fat storage. Further, we identify a previously unrecognized sex-biased role for Akh in regulating whole-body triglyceride levels.

In this study, we used the fruit fly Drosophila melanogaster to improve the knowledge of the mechanisms underlying the male-female difference in whole-body triglyceride levels. We show that the presence of a functional Tra protein in females, which directs many aspects of female sexual development, promotes whole-body fat storage. Tra’s ability to promote fat storage arises largely due to its function in neurons, where we identified the APCs as one neuronal population in which Tra function influences whole-body triglyceride levels. Our examination of Akh/AkhR mRNA levels and APC activity revealed several differences between the sexes, where these differences lead to higher Akh pathway activity in males than in females (Figure 7A and C). Genetic manipulation of APCs and Akh pathway activity suggest a model in which the sex bias in Akh pathway activity contributes to the male-female difference in fat storage by limiting whole-body triglyceride storage in males (Figure 7C). Importantly, we show that Tra function influences Akh pathway activity, and that Akh acts genetically downstream of Tra in regulating whole-body triglyceride levels (Figure 7B). This reveals a previously unrecognized genetic and physiological mechanism that contributes to the sex difference in fat storage.

Figure 7

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One key finding from our study was the identification of sex determination gene tra as an upstream regulator of the male-female difference in fat storage. In females, a functional Tra protein promotes fat storage, whereas lack of Tra in males leads to reduced fat storage. While an extensive body of literature has demonstrated important roles for tra in regulating neural circuits, behavior, abdominal pigmentation, and gonad development (Anand et al., 2001; Baker et al., 2001; Billeter et al., 2006; Brown and King, 1961; Burtis and Baker, 1989; Camara et al., 2008; Christiansen et al., 2002; Clough et al., 2014; Dauwalder, 2011; Demir and Dickson, 2005; Goodwin et al., 2000; Hall, 1994; Heinrichs et al., 1998; Hoshijima et al., 1991; Inoue et al., 1992; Ito et al., 1996; Nagoshi et al., 1988; Neville et al., 2014; Nojima et al., 2014; Pavlou et al., 2016; von Philipsborn et al., 2014; Pomatto et al., 2017; Rezával et al., 2014; Rezával et al., 2016; Rideout et al., 2007; Rideout et al., 2010; Ryner et al., 1996; Sturtevant, 1945), uncovering a role for tra in regulating fat storage significantly extends our understanding of how sex differences in metabolism arise. Given that sex differences exist in other aspects of metabolism (e.g., oxygen consumption) (Wat et al., 2020), this new insight suggests that more work will be needed to determine whether tra contributes to sexual dimorphism in additional metabolic traits. Indeed, one study showed that tra influences the sex difference in adaptation to hydrogen peroxide stress (Pomatto et al., 2017). Beyond metabolism, Tra also regulates multiple aspects of development and physiology such as intestinal stem cell proliferation (Ahmed et al., 2020; Hudry et al., 2016; Millington and Rideout, 2018), carbohydrate metabolism (Hudry et al., 2019), body size (Mathews et al., 2017; Rideout et al., 2015), phenotypic plasticity (Millington et al., 2021), and lifespan responses to dietary restriction (Regan et al., 2016). Because some, but not all, of these studies identify a cell type in which Tra function influences these diverse phenotypes, future studies will need to determine which cell types and tissues require Tra expression to establish a female metabolic and physiological state. Indeed, recent single-cell analyses reveal widespread gene expression differences in shared cell types between the sexes (Li et al., 2021).

Identifying neurons as the anatomical focus of Tra’s effects on fat storage was another key finding from our study. While many sexually dimorphic neural circuits related to behavior and reproduction have been identified (Anand et al., 2001; Auer and Benton, 2016; Baker et al., 2001; Billeter et al., 2006; Clyne and Miesenböck, 2008; Dauwalder, 2011; Demir and Dickson, 2005; Evans and Cline, 2007; Goodwin et al., 2000; Hall, 1994; Inoue et al., 1992; Ito et al., 1996; Kimura et al., 2019; Kvitsiani and Dickson, 2006; Neville et al., 2014; Nojima et al., 2014; Pavlou et al., 2016; von Philipsborn et al., 2014; Rezával et al., 2014; Rezával et al., 2016; Rideout et al., 2007; Rideout et al., 2010; Ryner et al., 1996; Sato et al., 2019; Shirangi et al., 2016; Wang et al., 2020), less is known about sex differences in neurons that regulate physiology and metabolism. Indeed, while many studies have identified neurons that regulate fat metabolism (Al-Anzi and Zinn, 2018; Al-Anzi et al., 2009; Chung et al., 2017; Li et al., 2016; May et al., 2020; Min et al., 2016; Mosher et al., 2015; Zhan et al., 2016), these studies were conducted in single- or mixed-sex populations. Because male-female differences in neuron number (Billeter et al., 2006; Castellanos et al., 2013; Demir and Dickson, 2005; Garner et al., 2017; Lee and Hall, 2001; Rideout et al., 2007; Rideout et al., 2010; Robinett et al., 2010; Taylor and Truman, 1992), morphology (Cachero et al., 2010; Kimura et al., 2019), activity (Guo et al., 2016), and connectivity (Cachero et al., 2010; Nojima et al., 2021) have all been described across the brain and ventral nerve cord (Mellert et al., 2010; Mellert et al., 2016), a detailed analysis of neuronal populations that influence metabolism will be needed in both sexes to understand how neurons contribute to the sex-specific regulation of metabolism and physiology. Indeed, while our identification of a role for APC sexual identity in regulating the male-female difference in fat storage represents a significant step forward in understanding how sex differences in neurons influence metabolic traits, more knowledge is needed of how Tra regulates sexual dimorphism in this critical neuronal subset. For example, while we show that females normally have lower Akh mRNA levels and APC activity, it remains unclear how the presence of Tra regulates these distinct traits. Tra may regulate Akh mRNA levels via known target genes fruitless (fru; FBgn0004652) and doublesex (dsx; FBgn0000504) (Burtis and Baker, 1989; Heinrichs et al., 1998; Hoshijima et al., 1991; Inoue et al., 1992; Nagoshi et al., 1988; Ryner et al., 1996), or alternatively through a fru- and dsx-independent pathway (Hudry et al., 2016; Rideout et al., 2015). To influence the sex difference in APC activity and Akh release, Tra may regulate factors such as ATP-sensitive potassium (K_ATP) channels and 5′ adenosine monophosphate-activated protein kinase (AMPK)-dependent signaling, both of which are known to modulate APC activity (Braco et al., 2012; Kim and Rulifson, 2004). Future studies will therefore need to investigate Tra-dependent changes to K_ATP channel expression and function in APCs, and characterize Tra’s effects on ATP levels and AMPK signaling within APCs.

Additional ways to learn more about the sex-specific regulation of fat storage by the APCs will include examining how sexual identity influences physical connections between the APCs and other neurons, and monitoring APC responses to circulating hormones. For example, there are physical connections between corazonin- and neuropeptide F (NPF; FBgn0027109)-positive (CN) neurons and APCs in adult male flies (Oh et al., 2019), and between the APCs and a bursicon-α-responsive subset of DLgr2 neurons in females (Scopelliti et al., 2019). These connections inhibit APC activity: CN neurons inhibit APC activity in response to high hemolymph sugar levels (Oh et al., 2019), whereas binding of bursicon-α to DLgr2 neurons inhibits APC activity in nutrient-rich conditions (Scopelliti et al., 2019). Future studies will therefore need to determine whether these physical connections exist in both sexes. Further, it will be important to identify male-female differences in circulating factors that regulate the APCs. While gut-derived Allatostatin C (AstC; FBgn0032336) was recently shown to bind its receptor on the APCs to trigger Akh release, loss of AstC affects fat metabolism and starvation resistance only in females (Kubrak et al., 2020). This suggests sex differences in AstC-dependent regulation of fat metabolism may exist.

Given that gut-derived NPF binds to its receptor on the APCs to inhibit Akh release (Yoshinari et al., 2021),that skeletal muscle-derived unpaired 2 (upd2; FBgn0030904) regulates hemolymph Akh levels (Zhao and Karpac, 2017), and that circulating peptides such as Allatostatin A (AstA; FBgn0015591), Drosophila insulin-like peptides (Dilps), and activin ligands influence Akh pathway activity (Ahmad et al., 2020; Hentze et al., 2015; Post et al., 2019; Song et al., 2017), it is clear that a systematic survey of circulating factors that modulate Akh production, release, and Akh pathway activity in each sex will be needed to fully understand the sex-specific regulation of fat storage. Another important point to address in future studies will be confirming results from previous studies that the fat body is the main anatomical focus of Akh-dependent regulation of fat storage (Bharucha et al., 2008; Grönke et al., 2007). Given that the sex-biased effects of triglyceride lipase bmm arise from a male-female difference in the cell type-specific requirements for bmm function (Wat et al., 2020), it will be important to determine which cell types mediate Akh’s effects on fat storage in each sex. This line of enquiry will also clarify the underlying processes that support increased fat storage in females. At present, it remains unclear whether the higher whole-body fat storage in females is caused by lower fat breakdown (Wat et al., 2020), increased lipogenesis, or both. Given that Akh pathway activity plays a role in regulating both lipolysis and lipogenesis in Drosophila and other insects (Grönke et al., 2007; Lee and Goldsworthy, 1995; Lorenz, 2003), it will be important to identify the cellular mechanism underlying Akh’s effects on the sex difference in fat storage.

Beyond fat metabolism, it will be important to extend our understanding of how sex-specific Akh regulation affects additional Akh-regulated phenotypes. Given that we and others show Akh affects fertility and fecundity (Liao et al., 2021), future studies will need to determine whether these phenotypes are due to Akh-dependent regulation of fat metabolism, or due to direct effects of Akh on gonads. Similarly, while Akh has been linked with the regulation of lifespan (Bednářová et al., 2018; Liao et al., 2021), carbohydrate metabolism (Kim and Rulifson, 2004; Lee and Park, 2004), starvation resistance (Isabel et al., 2005; Kubrak et al., 2020; Mochanová et al., 2018), locomotion (Isabel et al., 2005; Lee and Park, 2004), immune responses (Adamo et al., 2008), cardiac function (Isabel et al., 2005; Noyes et al., 1995), and oxidative stress responses (Gáliková et al., 2015), most studies were performed in mixed- or single-sex populations. Additional work is therefore needed to determine how changes to Akh pathway function affect physiology, carbohydrate levels, development, and life history in each sex. Importantly, the lessons we learn may also extend to other species. Akh signalling is highly conserved across invertebrates (Gäde and Auerswald, 2003; Lorenz and Gäde, 2009; Staubli et al., 2002), and is functionally similar to the mammalian β-adrenergic and glucagon systems (Grönke et al., 2007; Lee and Park, 2004; Staubli et al., 2002). Because sex-specific regulation of both glucagon and the β-adrenergic systems have been described in mammalian models and in humans (Al-Gburi et al., 2017; Bell et al., 2001; Bilginoglu et al., 2007; Brooks et al., 2015; Claustre et al., 1980; Dart et al., 2002; Davis et al., 2000; Drake et al., 1998; Freedman et al., 1987; Hinojosa-Laborde et al., 1999; Hoeker et al., 2014; Hogarth et al., 2007; Lafontan et al., 1997; Luzier et al., 1998; McIntosh et al., 2011; Ng et al., 1993), detailed studies on sex-specific Akh regulation and function in flies may provide vital clues into the mechanisms underlying male-female differences in physiology and metabolism in other animals.

Details of all statistical tests and p-values are in Supplementary file 1. All raw data generated in this study are in Supplementary file 2. All primer sequences are in Supplementary file 3. Fly food media recipe is in Supplementary file 4. Original image files for all images in this study are in their respective Source Data files.

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Author details

1. Lianna W Wat

   Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, Canada

   Contribution

   Conceptualization, Formal analysis, Investigation, Visualization, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6998-0594

2. Zahid S Chowdhury

   Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, Canada

   Contribution

   Conceptualization, Formal analysis, Investigation

   Competing interests

   No competing interests declared

3. Jason W Millington

   Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, Canada

   Contribution

   Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4330-2431

4. Puja Biswas

   Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, Canada

   Contribution

   Investigation

   Competing interests

   No competing interests declared

5. Elizabeth J Rideout

   Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, Canada

   Contribution

   Conceptualization, Funding acquisition, Project administration, Supervision, Validation, Writing – original draft, Writing – review and editing

   For correspondence

   elizabeth.rideout@ubc.ca

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0012-2828

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