The Internet Archive, an online repository of web pages, was offline Thursday after its founder confirmed a major cyberattack that exposed the data of millions of users and left the site defaced.

Toni Annala, Marc Hoyois and Ryomei Iwasa
J. Amer. Math. Soc. 38 (), 243-289.
Abstract, references and article information

Alexander Kupers and Oscar Randal-Williams
J. Amer. Math. Soc. 38 (), 63-178.
Abstract, references and article information

Junyi Xie
J. Amer. Math. Soc. 38 (), 1-62.
Abstract, references and article information

JP Segrest
Feb 1, 1992; 33:141-166
Reviews

Duterte’s Victory Is Cry for Help From Those Left Behind in Philippines Expert comment sysadmin 12 May 2016

But large support for mainstream parties and a mature democratic system should keep the country from slipping back towards authoritarianism.

The victory of political outsider Rodrigo Duterte in the 2016 Philippines’ elections is proof that a significant minority of the country’s population feels left behind by its recent economic success and estranged from its political elite. However the results of the elections as a whole suggest that most voters opted for a continuation of the current government’s policies.

Duterte looks almost certain to be inaugurated as the next president of the Philippines on 30 June. The country’s presidential voting system – a single round, first-past-the-post election – delivered victory to a populist outsider with 39 per cent support. Two candidates advocating a continuation of the current government’s policies − the Liberal Party’s Mar Roxas and independent Grace Poe − polled a combined 45 per cent. The long-standing factionalism within Philippines elite politics split the ‘anti-Duterte’ vote.

Changing the conversation

The contrast between Duterte and Roxas could hardly be greater. Mar Roxas is the grandson of the first president of an independent Philippines, a graduate of Wharton Business School and a former investment banker in the US. Rodrigo Duterte is a political outsider with an electoral base geographically almost as far from Manila as is possible to get in the Philippines: the city of Davao on the island of Mindanao.

The story of Duterte’s victory is the story of how ‘Duterte managed to change the national conversation from poverty towards crime and corruption,’ says Marites Vitug, editor-at-large of one of the Philippines’ most popular online news sites, Rappler. In January, Duterte was running fourth in opinion polls but a strategy that positioned him as the only opponent to the Manila elite gave him victory. This is the first time a provincial official has made it to the top job.

The headline figures tell us that the Philippines’ economy has done very well under President Benigno Aquino. Between 2010 and 2014, growth averaged 6.3 per cent per year. That fell to a still-impressive 5.8 per cent last year but is expected to pick up this year and next, according to the Asian Development Bank. Growth in agriculture, however, is significantly slower and rural areas feel left behind. While economic growth is benefiting the majority, inequality is worsening and resentment rising in poor villages. The contrast between the metropolitan sophistication of the Makati district in Manila and life in faraway provinces such as Duterte’s Mindanao is widening.

Ironically the Philippines’ economic success is a part of the explanation for the defeat of the ‘mainstream’ presidential candidates. Crime and corruption may have become more important issues simply because more voters have become better off and therefore more likely to be concerned about crime and corruption than before. It’s also undeniable that Duterte has a record for getting things done. Human rights groups rightly criticize his (at best) tolerance of the extra-judicial killing of alleged criminals but his repeated re-election as mayor demonstrates that many citizens are prepared to accept that in exchange for improved personal security. A surprising number of Manila residents have actually moved to Davao because of its better quality of life.

Traditional power bases

However, the results as a whole suggest a narrow majority in favour of current policies. In the vice-presidential race, the Liberal Party candidate Leni Robredo is narrowly ahead of Ferdinand ‘Bongbong’ Marcos, the son of the eponymous former president. Like Duterte she is regarded as a successful mayor of a well-run city, Albay. Duterte’s running mate Alan Cayetano received just 14 per cent of the vote.

In the senate election, Liberals won five of the 12 seats being contested, with a party- backed independent winning a sixth. The opposition, even with boxing champion and national idol Manny Pacquiao running for the United Nationalist Alliance, won four.

Taken as a whole, the results show the enduring nature of traditional Philippines power bases. The country’s many islands and distinct linguistic and cultural regions are virtual fiefs in which families and big bosses can wield almost total power through control of local authorities, businesses, the courts and security forces.

Threat to democracy?

It’s easy to forget that the election of Ferdinand Marcos in 1965 was originally welcomed as a challenge to the traditional elites of Philippine politics. The same accolades are currently greeting Duterte. Could they presage a return to the Philippines’ bad old days?

This seems less likely. Philippine democracy has matured considerably since Marcos declared martial law in 1972. There is a substantial, and vocal, middle class with experience of mobilizing against ‘bad’ presidents. There will also be pressures from international investors and the Philippines’ treaty ally, the United States, for better governance.

The Philippines will chair the Association of Southeast Asian Nations next year. That will put Duterte in the international spotlight as host of several international meetings – including the East Asia Summit attended by, among others, the presidents of China, Russia and the US. Since his victory Duterte has promised to act with decorum in office and declared that his election campaign antics were just a ploy to attract attention. Some leaders in Southeast Asia will use his victory to buttress their arguments against allowing their people to freely vote. It’s up to Duterte to decide whether he wants to be an advertisement for – or an argument against – democracy.

To comment on this article, please contact Chatham House Feedback

Demographics and politics

Analysing political trends based on demographics is growing as the global population changes and traditional political affiliations are replaced.

Major issues for Chatham House research include the impact of the growth of young people in the developing world, significant increases in population aging in the developed world, and the impact of increasing urbanization on political engagement.

Gender and diversity also play an important part in changing political attitudes, while predicting voting behaviour is becoming ever harder to do accurately, as the methods and technology used by younger generations to engage with politics differ hugely from more traditional approaches.

Víctor González-Aguilera, Alvaro Liendo, Pedro Montero and Roberto Villaflor Loyola
Trans. Amer. Math. Soc. 377 (), 5483-5511.
Abstract, references and article information

Christoforos Neofytidis
Trans. Amer. Math. Soc. 377 (), 5289-5321.
Abstract, references and article information

P. Lochak
St. Petersburg Math. J. 35 (), 477-535.
Abstract, references and article information

The subcellular localization of Arf family proteins is generally thought to be determined by their corresponding guanine nucleotide exchange factors. By promoting GTP binding, guanine nucleotide exchange factors induce conformational changes of Arf proteins exposing their N-terminal amphipathic helices, which then insert into the membranes to stabilize the membrane association process. Here, we found that the N-terminal amphipathic motifs of the Golgi-localized Arf family protein, Arfrp1, and the endosome- and plasma membrane–localized Arf family protein, Arl14, play critical roles in spatial determination. Exchanging the amphipathic helix motifs between these two Arf proteins causes the switch of their localizations. Moreover, the amphipathic helices of Arfrp1 and Arl14 are sufficient for cytosolic proteins to be localized into a specific cellular compartment. The spatial determination mediated by the Arfrp1 helix requires its binding partner Sys1. In addition, the residues that are required for the acetylation of the Arfrp1 helix and the myristoylation of the Arl14 helix are important for the specific subcellular localization. Interestingly, Arfrp1 and Arl14 are recruited to their specific cellular compartments independent of GTP binding. Our results demonstrate that the amphipathic motifs of Arfrp1 and Arl14 are sufficient for determining specific subcellular localizations in a GTP-independent manner, suggesting that the membrane association and activation of some Arf proteins are uncoupled.

Neutrophils are primary host innate immune cells defending against pathogens. One proposed mechanism by which neutrophils prevent the spread of pathogens is NETosis, the extrusion of cellular DNA resulting in neutrophil extracellular traps (NETs). The protease neutrophil elastase (NE) has been implicated in the formation of NETs through proteolysis of nuclear proteins leading to chromatin decondensation. In addition to NE, neutrophils contain three other serine proteases that could compensate if the activity of NE was neutralized. However, whether they do play such a role is unknown. Thus, we deployed recently described specific inhibitors against all four of the neutrophil serine proteases (NSPs). Using specific antibodies to the NSPs along with our labeled inhibitors, we show that catalytic activity of these enzymes is not required for the formation of NETs. Moreover, the NSPs that decorate NETs are in an inactive conformation and thus cannot participate in further catalytic events. These results indicate that NSPs play no role in either NETosis or arming NETs with proteolytic activity.

Stephanie E. Hood
Dec 1, 2020; 61:1720-1732
Research Articles

This manuscript has been withdrawn by the Author.

Functions of the gut microbiome have a growing number of implications for host metabolic health, with diet being one of the most significant influences on microbiome composition. Compelling links between diet and the gut microbiome suggest key roles for various macronutrients, including lipids, yet how individual classes of dietary lipids interact with the microbiome remains largely unknown. Sphingolipids are bioactive components of most foods and are also produced by prominent gut microbes. This makes sphingolipids intriguing candidates for shaping diet–microbiome interactions. Here, we used a click chemistry–based approach to track the incorporation of bioorthogonal dietary omega-alkynyl sphinganine (sphinganine alkyne [SAA]) into the murine gut microbial community (Bioorthogonal labeling). We identified microbial and SAA-specific metabolic products through fluorescence-based sorting of SAA-containing microbes (Sort), 16S rRNA gene sequencing to identify the sphingolipid-interacting microbes (Seq), and comparative metabolomics to identify products of SAA assimilation by the microbiome (Spec). Together, this approach, termed Bioorthogonal labeling-Sort-Seq-Spec (BOSSS), revealed that SAA assimilation is nearly exclusively performed by gut Bacteroides, indicating that sphingolipid-producing bacteria play a major role in processing dietary sphinganine. Comparative metabolomics of cecal microbiota from SAA-treated mice revealed conversion of SAA to a suite of dihydroceramides, consistent with metabolic activities of Bacteroides and Bifidobacterium. Additionally, other sphingolipid-interacting microbes were identified with a focus on an uncharacterized ability of Bacteroides and Bifidobacterium to metabolize dietary sphingolipids. We conclude that BOSSS provides a platform to study the flux of virtually any alkyne-labeled metabolite in diet–microbiome interactions.

Sphingolipids have emerged as bioactive lipids involved in the regulation of many physiological and pathological processes. In the retina, they have been established to participate in numerous processes, such as neuronal survival and death, proliferation and migration of neuronal and vascular cells, inflammation, and neovascularization. Dysregulation of sphingolipids is, therefore, crucial in the onset and progression of retinal diseases. This review examines the involvement of sphingolipids in retinal physiology and diseases. Ceramide (Cer) emerges as a common mediator of inflammation and death of neuronal and retinal pigment epithelium cells in animal models of retinopathies such as glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa. Sphingosine-1-phosphate (S1P) has opposite roles, preventing photoreceptor and ganglion cell degeneration but also promoting inflammation, fibrosis, and neovascularization in AMD, glaucoma, and pro-fibrotic disorders. Alterations in Cer, S1P, and ceramide-1-phosphate may also contribute to uveitis. Notably, use of inhibitors that either prevent Cer increase or modulate S1P signaling, such as Myriocin, desipramine, and Fingolimod (FTY720), preserves neuronal viability and retinal function. These findings underscore the relevance of alterations in the sphingolipid metabolic network in the etiology of multiple retinopathies and highlight the potential of modulating their metabolism for the design of novel therapeutic approaches.

The backbone of all sphingolipids (SLs) is a sphingoid long-chain base (LCB) to which a fatty acid is N-acylated. Considerable variability exists in the chain length and degree of saturation of both of these hydrophobic chains, and recent work has implicated ceramides with different LCBs and N-acyl chains in distinct biological processes; moreover, they may play different roles in disease states and possibly even act as prognostic markers. We now demonstrate that the half-life, or turnover rate, of ceramides containing diverse N-acyl chains is different. By means of a pulse-labeling protocol using stable-isotope, deuterated free fatty acids, and following their incorporation into ceramide and downstream SLs, we show that very-long-chain (VLC) ceramides containing C24:0 or C24:1 fatty acids turn over much more rapidly than long-chain (LC) ceramides containing C16:0 or C18:0 fatty acids due to the more rapid metabolism of the former into VLC sphingomyelin and VLC hexosylceramide. In contrast, d16:1 and d18:1 ceramides show similar rates of turnover, indicating that the length of the sphingoid LCB does not influence the flux of ceramides through the biosynthetic pathway. Together, these data demonstrate that the N-acyl chain length of SLs may not only affect membrane biophysical properties but also influence the rate of metabolism of SLs so as to regulate their levels and perhaps their biological functions.

Sphingolipids have become established participants in the pathogenesis of obesity and its associated maladies. Sphingosine kinase 1 (SPHK1), which generates S1P, has been shown to increase in liver and adipose of obese humans and mice and to regulate inflammation in hepatocytes and adipose tissue, insulin resistance, and systemic inflammation in mouse models of obesity. Previous studies by us and others have demonstrated that global sphingosine kinase 1 KO mice are protected from diet-induced obesity, insulin resistance, systemic inflammation, and NAFLD, suggesting that SPHK1 may mediate pathological outcomes of obesity. As adipose tissue dysfunction has gained recognition as a central instigator of obesity-induced metabolic disease, we hypothesized that SPHK1 intrinsic to adipocytes may contribute to HFD-induced metabolic pathology. To test this, we depleted Sphk1 from adipocytes in mice (SK1^fatKO) and placed them on a HFD. In contrast to our initial hypothesis, SK1^fatKO mice displayed greater weight gain on HFD and exacerbated impairment in glucose clearance. Pro-inflammatory cytokines and neutrophil content of adipose tissue were similar, as were levels of circulating leptin and adiponectin. However, SPHK1-null adipocytes were hypertrophied and had lower basal lipolytic activity. Interestingly, hepatocyte triacylglycerol accumulation and expression of pro-inflammatory cytokines and collagen 1a1 were exacerbated in SK1^fatKO mice on a HFD, implicating a specific role for adipocyte SPHK1 in adipocyte function and inter-organ cross-talk that maintains overall metabolic homeostasis in obesity. Thus, SPHK1 serves a previously unidentified essential homeostatic role in adipocytes that protects from obesity-associated pathology. These findings may have implications for pharmacological targeting of the SPHK1/S1P signaling axis.

Multiple sclerosis (MS) is a CNS disease characterized by immune-mediated demyelination and progressive axonal loss. MS-related CNS damage and its clinical course have two main phases: active and inactive/progressive. Reliable biomarkers are being sought to allow identification of MS pathomechanisms and prediction of its course. The purpose of this study was to identify sphingolipid (SL) species as candidate biomarkers of inflammatory and neurodegenerative processes underlying MS pathology. We performed sphingolipidomic analysis by HPLC-tandem mass spectrometry to determine the lipid profiles in post mortem specimens from the normal-appearing white matter (NAWM) of the normal CNS (nCNS) from subjects with chronic MS (active and inactive lesions) as well as from patients with other neurological diseases. Distinctive SL modification patterns occurred in specimens from MS patients with chronic inactive plaques with respect to NAWM from the nCNS and active MS (Ac-MS) lesions. Chronic inactive MS (In-MS) lesions were characterized by decreased levels of dihydroceramide (dhCer), ceramide (Cer), and SM subspecies, whereas levels of hexosylceramide and Cer 1-phosphate (C1P) subspecies were significantly increased in comparison to NAWM of the nCNS as well as Ac-MS plaques. In contrast, Ac-MS lesions were characterized by a significant increase of major dhCer subspecies in comparison to NAWM of the nCNS. These results suggest the existence of different SL metabolic pathways in the active versus inactive phase within progressive stages of MS. Moreover, they suggest that C1P could be a new biomarker of the In-MS progressive phase, and its detection may help to develop future prognostic and therapeutic strategies for the disease.

Fabry disease is caused by deficient activity of α-galactosidase A, an enzyme that hydrolyzes the terminal α-galactosyl moieties from glycolipids and glycoproteins, and subsequent accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb₃), globotriaosylsphingosine (lyso-Gb₃), and galabiosylceramide. However, there is no known link between these compounds and disease severity. In this study, we compared Gb₃ isoforms (various fatty acids) and lyso-Gb₃ analogs (various sphingosine modifications) in two strains of Fabry disease mouse models: a pure C57BL/6 (B6) background or a B6/129 mixed background, with the latter exhibiting more prominent cardiac and renal hypertrophy and thermosensation deficits. Total Gb₃ and lyso-Gb₃ levels in the heart, kidney, and dorsal root ganglion (DRG) were similar in the two strains. However, levels of the C20-fatty acid isoform of Gb₃ and particular lyso-Gb₃ analogs (+18, +34) were significantly higher in Fabry-B6/129 heart tissue when compared with Fabry-B6. By contrast, there was no difference in Gb₃ and lyso-Gb₃ isoforms/analogs in the kidneys and DRG between the two strains. Furthermore, using immunohistochemistry, we found that Gb₃ massively accumulated in DRG mechanoreceptors, a sensory neuron subpopulation with preserved function in Fabry disease. However, Gb₃ accumulation was not observed in nonpeptidergic nociceptors, the disease-relevant subpopulation that has remarkably increased isolectin-B4 (the marker of nonpeptidergic nociceptors) binding and enlarged cell size. These findings suggest that specific species of Gb₃ or lyso-Gb₃ may play major roles in the pathogenesis of Fabry disease, and that Gb₃ and lyso-Gb₃ are not responsible for the pathology in all tissues or cell types.

Lipins are eukaryotic proteins with functions in lipid synthesis and the homeostatic control of energy balance. They execute these functions by acting as phosphatidate phosphatase enzymes in the cytoplasm and by changing gene expression after translocation into the cell nucleus, in particular under fasting conditions. Here, we asked whether nuclear translocation and the enzymatic activity of Drosophila Lipin serve essential functions and how gene expression changes, under both fed and fasting conditions, when nuclear translocation is impaired. To address these questions, we created a Lipin null mutant, a mutant expressing Lipin lacking a nuclear localization signal (Lipin^NLS), and a mutant expressing enzymatically dead Lipin. Our data support the conclusion that the enzymatic but not nuclear gene regulatory activity of Lipin is essential for survival. Notably, adult Lipin^NLS flies were not only viable but also exhibited improved life expectancy. In contrast, they were highly susceptible to starvation. Both the improved life expectancy in the fed state and the decreased survival in the fasting state correlated with changes in metabolic gene expression. Moreover, increased life expectancy of fed flies was associated with a decreased metabolic rate. Interestingly, in addition to metabolic genes, genes involved in feeding behavior and the immune response were misregulated in Lipin^NLS flies. Altogether, our data suggest that the nuclear activity of Lipin influences the genomic response to nutrient availability with effects on life expectancy and starvation resistance. Thus, nutritional or therapeutic approaches that aim at lowering nuclear translocation of lipins in humans may be worth exploring.

During Drosophila oogenesis, the localization and translational regulation of maternal transcripts relies on RNA-binding proteins (RBPs). Many of these RBPs localize several mRNAs and may have additional direct interaction partners to regulate their functions. Using immunoprecipitation from whole Drosophila ovaries coupled to mass spectrometry, we examined protein-protein associations of 6 GFP-tagged RBPs expressed at physiological levels. Analysis of the interaction network and further validation in human cells allowed us to identify 26 previously unknown associations, besides recovering several well characterized interactions. We identified interactions between RBPs and several splicing factors, providing links between nuclear and cytoplasmic events of mRNA regulation. Additionally, components of the translational and RNA decay machineries were selectively co-purified with some baits, suggesting a mechanism for how RBPs may regulate maternal transcripts. Given the evolutionary conservation of the studied RBPs, the interaction network presented here provides the foundation for future functional and structural studies of mRNA localization across metazoans.

We developed a simple and rapid method to enrich protein N-terminal peptides, in which the protease TrypN is first employed to generate protein N-terminal peptides without Lys or Arg and internal peptides with two positive charges at their N-termini, and then the N-terminal peptides with or without N-acetylation are separated from the internal peptides by strong cation exchange chromatography according to a retention model based on the charge/orientation of peptides. This approach was applied to 20 μg of human HEK293T cell lysate proteins to profile the N-terminal proteome. On average, 1,550 acetylated and 200 unmodified protein N-terminal peptides were successfully identified in a single LC/MS/MS run with less than 3% contamination with internal peptides, even when we accepted only canonical protein N-termini registered in the Swiss-Prot database. Since this method involves only two steps, protein digestion and chromatographic separation, without the need for tedious chemical reactions, it should be useful for comprehensive profiling of protein N-termini, including proteoforms with neo-N-termini.

The Phillies continued to bolster their infield depth on Friday by signing versatile veteran Sean Rodriguez to a Minor League contract with an invite to big league Spring Training, MLB.com has learned.

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Phillies pitchers and catchers have their first workout Wednesday morning at Carpenter Complex. Almost anything can happen between Wednesday and Opening Day. That said, here is a very early prediction of the Phillies' Opening Day roster, knowing the Phillies remain in the hunt to sign Bryce Harper or Manny Machado.

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Phillies manager Gabe Kapler believes the two most important spots in a lineup are the Nos. 2 and 4 holes. Rhys Hoskins and Carlos Santana hit there most of last season. But with J.T. Realmuto, Andrew McCutchen and Jean Segura joining the Phillies in the offseason, Kapler has more options.

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The next five weeks will see lots of shuffling on Major League rosters. Here are the most intriguing positional battles on each of the 30 MLB clubs.

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Linebacker Quinton Bell and Miami Dolphins defenders deleted drives and put the Los Angeles Rams offense in quicksand, holding them without a touchdown to propel a primetime victory and snap a three-game losing streak.

Noritaka Hoshi, Senior Manager, AI Platform Division, talks about the impetus for and challenges within the development of SX-Aurora TSUBASA or a massive SIMD, created to handle enormous computing and […]

The post Advance Science, Technology and Sophistication with SX-Aurora TSUBASA or Vector Processor or Vector Engine (VE) appeared first on HPCwire.

Mattel has apologized after inadvertently directing customers of its new line of Wicked dolls to a pornographic website, stating it is taking action to remove the misprinted toys' packaging.

Air Force Special Operations aims to test the MC-130J Hercules transport aircraft's amphibious capability in 2022, the commander said Monday.

Animal behavior expert Philip Johns introduces us to the vibrant urban environments of Singapore, where city dwellers and skyscrapers coexist with a rich array of other species, including otters, hornbills and lizards — prompting the question: Can we design cities to be wildlife refuges?

Hopson became the interim superintendent in Shelby County, Tenn., in 2013 after the Memphis City School system merged with Shelby County schools. That merger then led six suburban communities to break away from the merged school system to form their own school districts.

Yulia Lerner
Feb 23, 2011; 31:2906-2915
BehavioralSystemsCognitive

Aggression involves both sexually monomorphic and dimorphic actions. How the brain implements these two types of actions is poorly understood. We found that in Drosophila melanogaster, a set of neurons, which we call CL062, previously shown to mediate male aggression also mediate female aggression. These neurons elicit aggression acutely and without the presence of a target. Although the same set of actions is elicited in males and females, the overall behavior is sexually dimorphic. The CL062 neurons do not express fruitless, a gene required for sexual dimorphism in flies, and expressed by most other neurons important for controlling fly aggression. Connectomic analysis in a female electron microscopy dataset suggests that these neurons have limited connections with fruitless expressing neurons that have been shown to be important for aggression and signal to different descending neurons. Thus, CL062 is part of a monomorphic circuit for aggression that functions parallel to the known dimorphic circuits.