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There is growing evidence that corporate market power is increasing and affecting monetary policy transmission. This paper develops a partial equilibrium model that highlights the role of financial constraints in shaping the role of markups for the response of firms to monetary policy shocks. We find support for such a role using a large cross-country firm-level dataset for 14 advanced economies.

Supplementary Figure S1. CREBBP binds to GC-specific super-enhancers. Supplementary Figure S2. Crebbp and EP300 expression in the B cell subsets development in Crebbpfl/flCγ1-Cre and Crebbpfl/flCD19-Cre mice. Supplementary Figure S3. GSEA analysis of Crebbpfl/fl vs Crebbp+/+ Cγ1-Cre GC B cells. Supplementary Figure S4. Analysis of GC B cell responses in the Cγ1-Cre and CD19-Cre cohorts. Supplementary Figure S5. Analysis of plasma cell differentiation in the Cγ1-Cre and CD19-Cre cohorts. Supplementary Figure S6. Distribution pattern of CREBBP mutations in FL and de novo DLBCL. Supplementary Figure S7. Analysis of Crebbp-conditional knockout cohorts. Supplementary Table S1. Overlap between CREBBP bound regions and predicted superenhancers in GC B cells. Supplementary Table S2. Genes differentially expressed in Crebbpfl/fl vs Crebbp+/+ GC B cells. Supplementary Table S3. List of CREBBP "core target" genes (bound by CREBBP in human GC B cells and downregulated in Crebbpfl/flCγ1-Cre GC B cells). Supplementary Table S4. Pathway enrichment analysis of CREBBP "core target" genes (bound by CREBBP in human GC B cells and downregulated in Cγ1-Cre Crebbpfl/fl GC B cells). Supplementary Table S5. Leading edge associated with GSEA of CREBBP core target genes in the rank of genes differentially expressed in DZ vs LZ GC B cells. Supplementary Table S6. Pathway enrichment analysis of genes co-bound by CREBBP and BCL6 in human GC B cells. Supplementary Table S7. V gene rearrangement analysis of B-cell lymphomas in the Crebbpfl/f/Cγ1-Cre /VavP-Bcl2 conditional knock-out mouse model. Supplementary Table S8. List of antibodies used in FACS analysis.

Heterozygous inactivating mutations of the KMT2D methyltransferase and the CREBBP acetyltransferase are among the most common genetic alterations in B cell lymphoma and co-occur in 40 to 60% of follicular lymphoma (FL) and 30% of EZB/C3 diffuse large B cell lymphoma (DLBCL) cases, suggesting they may be coselected. Here, we show that combined germinal center (GC)–specific haploinsufficiency of Crebbp and Kmt2d synergizes in vivo to promote the expansion of abnormally polarized GCs, a common preneoplastic event. These enzymes form a biochemical complex on select enhancers/superenhancers that are critical for the delivery of immune signals in the GC light zone and are only corrupted upon dual Crebbp / Kmt2d loss, both in mouse GC B cells and in human DLBCL. Moreover, CREBBP directly acetylates KMT2D in GC-derived B cells, and, consistently, its inactivation by FL/DLBCL-associated mutations abrogates its ability to catalyze KMT2D acetylation. Genetic and pharmacologic loss of CREBBP and the consequent decrease in KMT2D acetylation lead to reduced levels of H3K4me1, supporting a role for this posttranslational modification in modulating KMT2D activity. Our data identify a direct biochemical and functional interaction between CREBBP and KMT2D in the GC, with implications for their role as tumor suppressors in FL/DLBCL and for the development of precision medicine approaches targeting enhancer defects induced by their combined loss.

Non-artemisinin phytochemicals from Artemisia annua and A. afra infusions may explain their activity against the drug-refractory hypnozoite and mature gametocyte stages of Plasmodium parasites, potentially constituting invaluable antimalarial hits.

The political economy literature has put forward a multitude of hypotheses regarding the drivers of structural reforms, but few, if any, empirically robust findings have emerged thus far. To make progress, we draw a parallel with model uncertainty in the growth literature and provide a new version of the Bayesian averaging of maximum likelihood estimates (BAMLE) technique tailored to binary logit models. Relying on a new database of major past labor and product market reforms in advanced countries, we test a large set of variables for robust correlation with reform in each area. We find widespread support for the crisis‐induces‐reform hypothesis, as high unemployment and economic crises are robustly correlated to structural reforms. We also find evidence of reform convergence—that is, countries with tighter regulation are more prone to liberalize. Reforms are more likely when other countries also undertake them and when there is formal pressure to implement them. Other robust correlates are more specific to certain areas—for example, international pressure and political factors are most relevant for product market and job protection reforms, respectively.

The paper sheds light on the issue of how fast product market deregulation pays off and whether it entails any transitory costs by using a unique mapping between a new narrative dataset of major reform events and sector-level outcomes for 5 major non-manufacturing industries in 26 advanced economies over the period 1975–2011. Using a local projection method, we find that deregulation pays off only gradually: its positive effect on output becomes statistically significant three to four years after the reform, consistent with the notion that entry takes time due to real frictions. At the same time, there is no evidence of any significant transitory cost. Over the medium term, these product market reforms eventually yield large, highly significant increases in output, concomitant with a relative price decline. The typical major historical reform in advanced economies increased real value added and employment in the deregulated industry by about 10 percent and over 5 percent, respectively, and lowered relative prices by some 8 to 10 percent, after five years.

The alkaloid tazopsine 1 was introduced in the late 2000's as a novel antiplasmodial hit compound active against Plasmodium falciparum hepatic stages, with potential to develop prophylactic drugs based on this novel chemical scaffold. However, the structural determinants of tazopsine 1 bioactivity, together with the exact definition of the pharmacophore, remained elusive, impeding further development. We found that the antitussive drug dextromethorphan (DXM) 3, although lacking the complex pattern of stereospecific functionalization of the natural hit, was harboring significant antiplasmodial activity in vitro despite suboptimal prophylactic activity in a murine model of malaria, which precluded its direct repurposing against malaria. The targeted N-alkylation of nor-DXM 15 delivered a small library of analogues with greatly improved activity over DXM 3 against P. falciparum asexual stages. Amongst these, N-2’-pyrrolylmethyl-nor-DXM 16i showed a 2- to 36-fold superior inhibitory potency compared to tazopsine 1 and DXM 3 against parasite liver and blood stages, with 760 ± 130 nM and 2.1 ± 0.4 µM IC50 values, respectively, as well as liver/blood phase selectivity of 2.8. Furthermore, cpd. 16i showed a 5 to 8-fold increase of activity relatively to DXM 3 against P. falciparum stages I-II and V gametocytes, with 18.5 µM and 13.2 µM IC50 values, respectively. Cpd. 16i can thus be considered a promising novel hit compound against malaria in the ent-morphinan series with putative pan-cycle activity, paving the way for further therapeutic development (e. g., investigation of its prophylactic activity in a mouse model of malaria).

We explore the impact of major labor and product market reforms on current account dynamics using a new “narrative” database of major changes in employment protection for regular workers and product market regulation for non-manufacturing industries covering 26 advanced economies over the past four decades. Our main finding is that product market deregulation is associated with a weakening of the current account, while labor market deregulation is associated with an improvement. These effects are transitory and driven by both saving and investment responses. Labor and product market reforms both have a more positive impact on the current account balance when implemented under weak macroeconomic conditions. Our results are broadly consistent with predictions from recent DSGE models with endogenous producer entry and labor market frictions.

The alkaloid tazopsine

Artemisinin-based combination therapies (ACT) are the frontline treatments against malaria worldwide. Recently the use of traditional infusions fromArtemisia annua(from which artemisinin is obtained) orA. afra(lacking artemisinin) has been controversially advocated. Such unregulated plant-based remedies are strongly discouraged as they might constitute sub-optimal therapies and promote drug resistance. Here, we conducted the first comparative study of the anti-malarial effects of both plant infusionsin vitroagainst the asexual erythrocytic stages ofP. falciparumand the pre-erythrocytic (i. e., liver) stages of variousPlasmodiumspecies. Low concentrations of either infusion accounted for significant inhibitory activities across every parasite species and stage studied. We show that these antiplasmodial effects were essentially artemisinin-independent and were additionally monitored by observations of the parasite apicoplast and mitochondrion. In particular, the infusions significantly incapacitated sporozoites, and forP. vivaxandP. cynomolgi,disrupted the hypnozoites. This provides the first indication that compounds other than 8-aminoquinolines could be effective antimalarials against relapsing parasites. These observations advocate for further screening to uncover urgently needed novel antimalarial lead compounds.

We analyze the potential role of equity injections in addressing solvency risks among small and medium-sized enterprises (SMEs) after the COVID-19 crisis. Building on firm-level balance sheet projections for a sample of European economies, we simulate selected policy interventions and find that equity injections are quite effective at dampening the rise in insolvencies. Cost effectiveness requires careful targeting, however; under an illustrative scenario, leaving aside any costs arising from imperfect information and implementation, the cost of a program targeting only those SMEs worth saving is just a tenth of the cost of an untargeted approach directed to all insolvent firms. Overall, our paper provides a case for governments to rely more on targeted equity injections in responding to major shocks that trigger mass solvency risks.

Infusions from two Artemisia species, one containing artemisinin, the other not, equally inhibit pre-erythrocytic and erythrocytic stages of different Plasmodium species, including two relapsing species., Artemisinin-based combination therapies (ACT) are the frontline treatments against malaria worldwide. Recently the use of traditional infusions from Artemisia annua (from which artemisinin is obtained) or Artemisia afra (lacking artemisinin) has been controversially advocated. Such unregulated plant-based remedies are strongly discouraged as they might constitute sub-optimal therapies and promote drug resistance. Here, we conducted the first comparative study of the anti-malarial effects of both plant infusions in vitro against the asexual erythrocytic stages of Plasmodium falciparum and the pre-erythrocytic (i.e., liver) stages of various Plasmodium species. Low concentrations of either infusion accounted for significant inhibitory activities across every parasite species and stage studied. We show that these antiplasmodial effects were essentially artemisinin-independent and were additionally monitored by observations of the parasite apicoplast and mitochondrion. In particular, the infusions significantly incapacitated sporozoites, and for Plasmodium vivax and P. cynomolgi, disrupted the hypnozoites. This provides the first indication that compounds other than 8-aminoquinolines could be effective antimalarials against relapsing parasites. These observations advocate for further screening to uncover urgently needed novel antimalarial lead compounds.

A fluorogenic benzochalcone specifically labels live neutrophil granules in whole wild-type, GFP- or RFP-expressing zebrafish embryos and larvae., Neutrophil granules (NGs) are key components of the innate immune response and mark the development of neutrophilic granulocytes in mammals. However, there has been no specific fluorescent vital stain up to now to monitor their dynamics within a whole live organism. We rationally designed a benzochalcone fluorescent probe (HAB) featuring high tissue permeability and optimal photophysics such as elevated quantum yield, pronounced solvatochromism and target-induced fluorogenesis. Phenotypic screening identified HAB as the first cell- and organelle-specific small-molecule fluorescent tracer of NGs in live zebrafish larvae, with no labeling of other cell types or organelles. HAB staining was independent of the state of neutrophil activation, labeling NGs of both resting and phagocytically active neutrophils with equal specificity. By high-resolution live imaging, we documented the dynamics of HAB-stained NGs during phagocytosis. Upon zymosan injection, labeled NGs were rapidly recruited to the forming phagosomes. Despite being a reversible ligand, HAB could not be displaced by high concentrations of pharmacologically relevant competing chalcones, indicating that this specific labeling was the result of the HAB's precise physicochemical signature rather than a general feature of chalcones. However, one of the competitors was discovered as a promising interstitial fluorescent tracer illuminating zebrafish histology, similarly to BODIPY-ceramide. As a yellow-emitting histopermeable vital stain, HAB functionally and spectrally complements most genetically incorporated fluorescent tags commonly used in live zebrafish biology, holding promise for the study of neutrophil-dependent responses relevant to human physiopathology such as developmental defects, inflammation and infection. Furthermore, HAB intensely labeled isolated live human neutrophils at the level of granulated subcellular structures consistent with human NGs, suggesting that the labeling of NGs by HAB is not restricted to the zebrafish model but also relevant to mammalian systems.

Corporate market power has risen in recent decades, and new estimates in this note suggest that the likely wave of small and medium-sized enterprise bankruptcies from the ongoing pandemic will further strengthen market concentration. Whether and how policymakers should address this issue is hotly debated. This note provides new evidence on the policy relevance of rising market power and highlights possible implications for the design of competition policy frameworks and macroeconomic policies.

To ensure the transport of nutrients necessary for their survival,Plasmodium falciparumparasites increase erythrocyte permeability to diverse solutes. These New Permeation Pathways (NPP) have been extensively characterized in the pathogenic asexual parasite stages, however the existence of NPP has never been investigated in gametocytes, the sexual stages responsible for transmission to mosquitoes. Here, we show that NPP are still active in erythrocytes infected with immature gametocytes and that this activity declines along gametocyte maturation. Our results indicate that NPP are regulated by cyclic AMP (cAMP) signaling cascade during sexual parasite stages, and that the decrease in cAMP levels in mature stages results in a slowdown of NPP activity. We also show that NPP facilitate the uptake of artemisinin derivatives and that phosphodiesterase (PDE) inhibitors can reactivate NPP and increase drug uptake in mature gametocyte-infected erythrocytes. These processes are predicted to play a key role inP. falciparumgametocyte biology and susceptibility to antimalarials.

Three novel tracers designed as fluorescent surrogates of artemisinin-derived antimalarial drugs (i.e., dihydroartemisinin, artemether, arteether, and artemisone) were synthesized from dihydroartemisinin. One of these tracers, corresponding to a dihydroartemisinin/artemether/arteether mimic, showed a combination of excellent physicochemical and biological properties such as hydrolytic stability, high inhibitory potency against blood-stage parasites, similar ring-stage survival assay values than the clinical antimalarials, high cytopermeability and specific labeling of live P. falciparum cells, alkylation of heme, as well as specific covalent labeling of drug-sensitive and drug-resistant P. falciparum proteomes at physiological concentrations, consistent with a multitarget action of the drugs. Our study demonstrates that probes containing the complete structural core of clinical artemisinin derivatives can be stable in biochemical and cellular settings, and recapitulate the complex mechanisms of these frontline, yet threatened, antimalarial drugs.

anais.laleve@inrae.frgenevieve.dujardin@i2bc.paris-saclay.fr; International audience; Artemisinin and its derivatives kill malaria parasites and inhibit the proliferation of cancer cells. In both processes, heme was shown to play a key role in artemisinin bioactivation. We found that artemisinin and clinical artemisinin derivatives are able to compensate for a mutation in the yeast Bcs1 protein, a key chaperon involved in biogenesis of the mitochondrial respiratory complex III. The equivalent Bcs1 variant causes an encephalopathy in human by affecting complex III assembly. We show that artemisinin derivatives decrease the content of mitochondrial cytochromes and disturb the maturation of the complex III cytochrome c1. This last effect is likely responsible for the compensation by decreasing the detrimental over-accumulation of the inactive pre-complex III observed in the bcs1 mutant. We further show that a fluorescent dihydroartemisinin probe rapidly accumulates in the mitochondrial network and targets cytochromes c and c1 in yeast, human cells and isolated mitochondria. In vitro this probe interacts with purified cytochrome c only under reducing conditions and we detected cytochrome c-dihydroartemisinin covalent adducts by mass spectrometry analyses. We propose that reduced mitochondrial c-type cytochromes act as both targets and mediators of artemisinin bioactivation in yeast and human cells.

While there is growing evidence of persistent or even permanent output losses from financial crises, the causes remain unclear. One candidate is intangible capital – a rising driver of economic growth that, being non-pledgeable as collateral, is vulnerable to financial frictions. By sheltering intangible investment from financial shocks, counter-cyclical macroeconomic policy could strengthen longer-term growth, particularly so where strong product market competition prevents firms from self-financing their investments through rents. Using a rich cross-country firm-level dataset and exploiting heterogeneity in firm-level exposure to the sharp and unforeseen tightening of credit conditions around September 2008, we find strong support for these theoretical predictions. The quantitative implications are large, highlighting a powerful stabilizing role for macroeconomic policy through the intangible investment channel, and its complementarity with pro-competition product market deregulation.

This paper reassesses the impact of trade liberalization on productivity. We build a new, unique database of effective tariff rates at the country‐industry level for a broad range of countries over the past two decades. We then explore both the direct effect of liberalization in the sector considered, as well as its indirect impact in downstream industries via input linkages. Our findings point to a dominant role of the indirect input market channel in fostering productivity gains. A 1 percentage point decline in input tariffs is estimated to increase total factor productivity by about 2 percent in the sector considered. For advanced economies, the implied potential productivity gains from fully eliminating remaining tariffs are estimated at around 1 percent, on average, which do not factor in the presumably larger gains from removing existing non‐tariff barriers. Finally, we find suggestive evidence of complementarities between trade and FDI liberalization in boosting productivity. This calls for a broad liberalization agenda that cuts across different areas.

International audience; Artemisinin is the most widely-used compound against malaria and plays a critical role in the treatment of malaria worldwide. Resistance to artemisinin emerged about a decade ago in Southeast Asia and it is paramount to prevent its spread or emergence in Africa. Artemisinin has a complex mode of action and can cause widespread injury to many components of the parasite. In this review, we outline the different metabolic pathways affected by artemisinin, including the unfolded protein response, protein polyubiquitination, proteasome, phosphatidylinositol-3-kinase, and the eukaryotic translation initiation factor 2α. Based on recently published data, we present a model of how these different pathways interplay and how mutations in K13, the main identified resistance marker, may help parasites survive under artemisinin pressure.

Le phenotype erythrocytaire Emm- a ete decrit en 1973 mais reste l’un des derniers groupes sanguins de base genetique inconnue (antigene de prevalence elevee de la serie 901). Il avait ete propose qu’Emm serait porte par une proteine ancree a la membrane du globule rouge (GR) par un glycosylphosphatidylinositol (GPI) car l’expression de cet antigene est fortement reduite dans les GRs de patients atteints d’hemoglobinurie paroxystique nocturne (HPN). Cette maladie est causee par des mutations somatiques du gene PIGA, implique dans la synthese du GPI. En utilisant une approche genomique basee sur le sequencage d’exome chez 3 rarissimes individus Emm- (dont le cas index), nous avons identifie des mutations homozygotes sur un gene commun implique dans la synthese du GPI, PIGG. En utilisant l’approche Crispr/Cas-9, nous avons developpe des lignees cellulaires deficientes pour plusieurs genes PIGs impliques dans la synthese et le trafic des proteines ancrees au GPI. L’analyse de ces cellules par cytometrie en flux et western blot en utilisant un anticorps anti-Emm a montre que Emm est porte par un GPI libre et que l’epitope est forme par le 2e et 3e ethanolamine du squelette du GPI. Nous avons montre que l’anticorps anti-Emm detecte parfaitement les defauts de synthese du GPI, causes par des mutations germinales dans les genes PIGs et responsables de pathologies neurologiques severes. Il est a noter que le cas index etait atteint d’un deficit intellectuel et que l’absence de PIGG semble donc etre associee a des troubles du developpement du systeme nerveux central. Ce travail a permis d’etablir Emm comme un nouveau systeme de groupe sanguin chez l’Homme (n°42, ISBT 2020) ( Fig. 1 ).

CREBBP is targeted by inactivating mutations in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Here, we provide evidence from transgenic mouse models that Crebbp deletion results in deficits in B-cell development and can cooperate with Bcl2 overexpression to promote B-cell lymphoma. Through transcriptional and epigenetic profiling of these B cells, we found that Crebbp inactivation was associated with broad transcriptional alterations, but no changes in the patterns of histone acetylation at the proximal regulatory regions of these genes. However, B cells with Crebbp inactivation showed high expression of Myc and patterns of altered histone acetylation that were localized to intragenic regions, enriched for Myc DNA binding motifs, andshowedMycbinding. Through the analysis ofCREBBPmutations from a large cohort of primary human FL and DLBCL, we show a significant difference in the spectrum of CREBBP mutations in these 2 diseases, with higher frequencies of nonsense/ frameshift mutations in DLBCL compared with FL. Together, our data therefore provide important links between Crebbp inactivation and Bcl2 dependence and show a role for Crebbp inactivation in the induction of Myc expression. We suggest this may parallel the role of CREBBP frameshift/nonsense mutations in DLBCL that result in loss of the protein, but may contrast the role of missense mutations in the lysine acetyltransferase domain that are more frequently observed in FL and yield an inactive protein., Research in the M.R.G. group is supported by grants from the Nebraska Department of Health and Human Services (LB506 2016-16) and the National Institutes of Health, National Cancer Institute (1R01CA201380). Research in the I.S.-G. group is partially supported by Fondo Europeo de Desarrollo Regional (FEDER) and by the Ministry of Economy and Competitiveness (SAF2012-32810, SAF2015-64420-R, and Red de Excelencia Consolider OncoBIO SAF2014-57791-REDC), Instituto de Salud Carlos III (PIE14/00066), Instituto de Salud Carlos III Plan de Ayudas Institute of Biomedical Research of Salamanca 2015 Proyectos Integrados (IBY15/00003), by Junta de Castilla y Leon (BIO/SA51/15, CSI001U14, UIC-017, andCSI001U16), Fundacion Inocente Inocente, by the German Carreras Foundation (Organisation der Deutsche Jose Carreras Leukamie-Stiftung eV R13/26), and by the Advanced Research on Interaction Mechanisms of electro Magnetic Exposures with Organisms for Risk Assessment project (European Union’s Seventh Framework Programme [FP7/2007-2013] under grant agreement no. 282891). The Nebraska Lymphoma Study Group tissue bank is supported by the Fred & Pamela Buffett Cancer Center’s National Cancer Institute Cancer Center Support Grant (P30CA036727). The I.S.-G. laboratory is a member of the EuroSyStem and the Developing Evidence to Inform Decisions about Effectiveness Network funded by the European Union under the FP7 program. Research in the C.V.-D. group is partially supported by a “Miguel Servet” Grant (CP14/00082, AES 2013-2016, FEDER) from the Instituto de Salud Carlos III (Ministerio de Economia y Competitividad). I.G.-R. was supported by BES-Ministerio de Economia y Competitividad (BES-2013-063789). G.R.-H. and L.R.-R. were supported by Fondo Social Europeo-Consejeria de Educacion de la Junta de Castilla y Leon. R.D. was supported by a fellowship from Region Ile de France (Appel hors DIM 2013). Research in the F.R.-L. group was supported by grants from Universite Paris Diderot, CNRS, Institut National du Cancer (2012-1-PL-BIO), and the Plan Cancer Environnement 2013. Ultrafast liquid chromatography analyses were done on the platform “Bioprofiler” (Unite de Biologie Fonctionnelle et Adaptative).

This paper explores the short-term employment effect of deregulating job protection for regular workers and how it varies with prevailing business cycle conditions. We apply the local projection method to a newly constructed dataset of major regular job protection reforms covering 26 advanced economies over the past four decades. The analysis relies on country-sector-level data, using as identifying assumption the fact that stringent dismissal regulations are more binding in sectors that are characterized by a higher ‘natural’ propensity to make regular adjustments to the workforce. We find that the response of sectoral employment to deregulation depends crucially on the state of the economy at the time of reform—deregulation increases employment if implemented during an economic expansion, but reduces employment if carried out in a recession. These findings are consistent with theory and are robust to a battery of sensitivity checks.

This paper discusses theoretical aspects and evidences related to designing labor market institutions in emerging market and developing economies. This note reviews the state of theory and evidence on the design of labor market institutions in a developing economy context and then reviews its consistency with actual labor market advice in a selected set of emerging and developing economies. The focus is mainly on three broad sets of institutions that matter for both workers’ protection and labor market efficiency: employment protection, unemployment insurance and social assistance, minimum wages and collective bargaining. Text mining techniques are used to identify IMF recommendations in these areas in Article IV Reports for 30 emerging and frontier economies over 2005–2016. This note has provided a critical review of the literature on the design of labor market institutions in emerging and developing market economies, and benchmarked the advice featured in IMF recommendations for 30 emerging market and frontier economies against the tentative conclusions from the literature.

International audience; Etoposide is a widely prescribed anticancer drug that is, however, associated with an increased risk of secondary leukemia. Although the molecular basis underlying the development of these leukemias remains poorly understood, increasing evidence implicates the interaction of etoposide metabolites [i.e., etoposide quinone (EQ)] with topoisomerase II enzymes. However, effects of etoposide quinone on other cellular targets could also be at play. We investigated whether T-cell protein tyrosine phosphatase (TCPTP), a protein tyrosine phosphatase that plays a key role in normal and malignant hematopoiesis through regulation of Janus kinase/signal transducer and activator of transcription signaling, could be a target of EQ. We report here that EQ is an irreversible inhibitor of TCPTP phosphatase (IC50 = similar to 7 mu M, second-order rate inhibition constant of similar to 810 M-1.min(-1)). No inhibition was observed with the parent drug. The inhibition by EQ was found to be due to the formation of a covalent adduct at the catalytic cysteine residue in the active site of TCPTP. Exposure of human hematopoietic cells (HL60 and Jurkat) to EQ led to inhibition of endogenous TCPTP and concomitant increase in STAT1 tyrosine phosphorylation. Our results suggest that in addition to alteration of topoisomerase II functions, EQ could also contribute to etoposide-dependent leukemogenesis through impairment of key hematopoietic signaling enzymes, such as TCPTP.

We study, both theoretically and empirically, how labor market regulation affects fiscal multipliers. We focus on the stringency of employment protection legislation, a prominent source of rigidity in European labor markets. First, using a small-open economy model that features labor-market search-and-matching frictions and nominal rigidities, we show that an increase in government spending has larger output effects when firing costs are lower. The importance of layoff costs for the public spending multiplier is larger in the absence of exchange rate adjustment and in a recession. Second, we confirm these findings empirically using a panel of 26 advanced countries over the period 1970–2013. The effect of job protection on fiscal multipliers is both statistically and economically significant.

This paper explores the effects of labor and product market reforms in a New Keynesian, small open economy model with labor market frictions and endogenous producer entry. We show that it takes time for reforms to pay off, typically at least a couple of years. This is partly because the benefits materialize through firm entry and increased hiring, both of which are gradual processes, while any reform-driven layoffs are immediate. Some reforms – such as reductions in employment protection – increase unemployment temporarily. Implementing a broad package of labor and product market reforms minimizes transition costs. Importantly, reforms do not have noticeable deflationary effects, suggesting that the inability of monetary policy to deliver large interest rate cuts in their aftermath – either because of the zero bound on policy rates or because of the membership in a monetary union – may not be a relevant obstacle to reform. Alternative simple monetary policy rules do not have a large effect on transition costs.

We study the consequences of product and labor market reforms in a two-country model with endogenous producer entry and labor market frictions. We focus on the role of business cycle conditions and external constraints at the time of reform implementation (or of a credible commitment to it) in shaping the dynamic effects of such policies. Product market reform is modeled as a reduction in entry costs and takes place in a non-traded sector that produces services used as input in manufacturing production. Labor market reform is modeled as a reduction in firing costs and/or unemployment benefits. We find that business cycle conditions at the time of deregulation significantly affect adjustment. A reduction of firing costs entails larger and more persistent adverse short-run effects on employment and output when implemented in a recession. By contrast, a reduction in unemployment benefits boosts employment and output by more in a recession compared to normal times. The impact of product market reforms is less sensitive to business cycle conditions. Credible announcements about future reforms induce sizable short-run dynamics, regardless of whether the announcement takes place in normal times or during an economic downturn. Whether the immediate effect is expansionary or contractionary varies across reforms. Finally, lack of access to international lending in the wake of reform can amplify the costs of adjustment.

Ever since Frankel and Rose's (1998) seminal paper, the literature on trade and business cycle synchronization has relied on gross trade data, with weak results in recent papers that carefully address omitted variable bias. This paper re-examines this relationship using new value-added trade data for 63 advanced and emerging economies during 1995–2013. In a panel framework, we identify a significantly positive impact of bilateral (value-added) trade intensity on business cycle synchronization—controlling for global common shocks, country-pair heterogeneity and other covariates—that is absent when gross trade data are used. There is also some evidence that the impact of value-added trade on synchronization increases with the degree of (value-added) intra-industry trade. We provide a theoretical rationale for the role of value-added trade for synchronization using a simple international business cycle model that features cross-country input linkages in production.

Aromatic amines (AAs) are chemicals of industrial, pharmacological and environmental relevance. Certain AAs, such as 4-aminobiphenyl (4-ABP), are human carcinogens that require enzymatic metabolic activation to reactive chemicals to form genotoxic DNA adducts. Arylamine N-acetyltransferases (NAT) are xenobiotic metabolizing enzymes (XME) that play a major role in this carcinogenic bioactivation process. Isothiocyanates (ITCs), including benzyl-ITC (BITC) and phenethyl-ITC (PEITC), are phytochemicals known to have chemopreventive activity against several aromatic carcinogens. In particular, ITCs have been shown to modify the bioactivation and subsequent mutagenicity of carcinogenic AA chemicals such as 4-ABP. However, the molecular and biochemical mechanisms by which these phytochemicals may modulate AA carcinogens bioactivation and AA-DNA damage remains poorly understood. This manuscript provides evidence indicating that ITCs can decrease the metabolic activation of carcinogenic AAs via the irreversible inhibition of NAT enzymes and subsequent alteration of the acetylation of AAs. We demonstrate that BITC and PEITC react with NAT1 and inhibit readily its acetyltransferase activity (k(i) = 200 M(-1).s(-1) and 66 M(-1).s(-1) for BITC and PEITC, respectively). Chemical labeling, docking approaches and substrate protection assays indicated that inhibition of the acetylation of AAs by NAT1 was due to the chemical modification of the enzyme active site cysteine. Moreover, analyses of AAs acetylation and DNA adducts in cells showed that BITC was able to modulate the endogenous acetylation and bioactivation of 4-ABP. In conclusion, we show that direct inhibition of NAT enzymes may be an important mechanism by which ITCs exert their chemopreventive activity towards AA chemicals.

The paper estimates the dynamic macroeconomic effects of labor and product market reforms on output, employment and productivity, and explores how these vary with prevailing macroeconomic conditions and policies. We apply a local projection method to a new dataset of major country- and country-sector-level reform shocks in various areas of labor market institutions and product market regulation covering 26 advanced economies over the past four decades. Product market reforms are found to raise productivity and output, but gains materialize only slowly. The impact of labor market reforms is primarily on employment, but it varies across types of reforms and depends on overall business cycle conditions - unlike that of product market reforms. Reductions in labor tax wedges and increases in public spending on active labor market policies have larger effects during periods of slack, in part because they usually entail some degree of fiscal stimulus. In contrast, reforms to employment protection arrangements and unemployment benefit systems have positive effects in good times, but can become contractionary in periods of slack. The economy's response to such reforms is significantly improved when they are accompanied by fiscal or monetary stimulus.

The political economy literature has put forward a multitude of hypotheses regarding the drivers of structural reforms, but few, if any, empirically robust findings have emerged thus far. To make progress, we draw a parallel with model uncertainty in the growth literature and provide a new version of the Bayesian averaging of maximum likelihood estimates (BAMLE) technique tailored to binary logit models. Relying on a new database of major past labor and product market reforms in advanced countries, we test a large set of variables for robust correlation with reform in each area. We find widespread support for the crisis-induces-reform hypothesis. Outside pressure increases the likelihood of reform in certain areas: reforms are more likely when other countries also undertake them and when there is formal pressure to implement them. Other robust correlates are more specific to certain areas—for example, international pressure and political factors are most relevant for product market and job protection reforms, respectively.

Labor market deregulation, intended to boost productivity and employment, is one plausible, yet little studied, driver of the decline in labor shares that took place across most advanced economies since the early 1990s. This paper assesses the impact of job protection deregulation in a sample of 26 advanced economies over the period 1970-2015, using a newly constructed dataset of major reforms to employment protection legislation for regular contracts. We apply the local projection method to estimate the dynamic response of the labor share to our reform events at both the country and the country-industry levels. For the latter, we employ a differences-in-differences identification strategy using two identifying assumptions grounded in theory—namely that job protection deregulation should have larger negative effects in industries characterized by (i) a higher “natural” propensity to adjust the workforce, and (ii) a lower elasticity of substitution between capital and labor. We find a statistically significant, economically large and robust negative effect of deregulation on the labor share. In particular, illustrative back-of-the-envelope calculations suggest that job protection deregulation may have contributed about 15 percent to the average labor share decline in advanced economies. Together with existing evidence regarding the macroeconomic gains from job protection and other labor market reforms, our results also point to the need for policymakers to address efficiency-equity trade-offs when designing such reforms.