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Transmission of Plasmodium falciparum and other malaria parasites requires their differentiation from asexual blood stages into gametocytes, the non-replicative sexual stage necessary to infect the mosquito vector. This transition involves changes in gene expression and chromatin reorganization that result in the activation and silencing of stage-specific genes. However, the genomes of malaria parasites have been noted for their limited number of transcriptional and chromatin regulators, and the molecular mediators of these changes remain largely unknown. We recently identified homeodomain protein 1 (HDP1) as a DNA-binding protein, first expressed in gametocytes, that enhances the expression of key genes critical for early sexual differentiation. The discovery of HDP1 marks a new class of transcriptional regulator in malaria parasites outside of the better-characterized ApiAP2 family. Here, using molecular biology, biochemistry and microscopy techniques, we show that HDP1 is essential for gametocyte maturation, facilitating the necessary upregulation of inner membrane complex components during early gametocytogenesis that gives P. falciparum gametocytes their characteristic shape. HDP1 is a novel DNA-binding protein that functions as a positive transcriptional regulator of genes that gives Plasmodium falciparum gametocytes their characteristic ‘banana’ shape.

Trehalose polyphleates (TPPs) are complex lipids associated with the mycobacterial cell surface and were identified 50 years ago. While the TPP biosynthetic pathway has been described recently, the role of these lipids in the biology of mycobacteria remains yet to be established. The wide distribution of TPPs across mycobacterial species suggests that they may exhibit important functions in these actinobacteria. Here, we demonstrate that Mycobacterium abscessus, an emerging multidrug-resistant pathogen that causes severe lung diseases in cystic fibrosis patients, requires TPPs for survival in macrophages and virulence in a zebrafish model of infection. These findings support the importance of this underexplored family of lipids in mycobacterial pathogenesis.

Toxoplasma gondii is a parasitic protist possessing a limited set of proteins involved in the autophagy pathway, a self-degradative machinery for protein and organelle recycling. This distant eukaryote has even repurposed part of this machinery, centered on protein ATG8, for a non-degradative function related to the maintenance of the apicoplast, a parasite-specific organelle. However, some evidence also suggest Toxoplasma is able to generate autophagic vesicles upon stress, and that some autophagy-related proteins, such as ATG9, might be involved solely in the canonical autophagy function. Here, we have characterised TgPROP1 and TgPROP2, two Toxoplasma proteins containing WD-40 repeat that can bind lipids for their recruitment to vesicular structures upon stress. They belong to the PROPPIN family and are homologues to ATG18/WIPI, which are known to be important for the autophagic process. We conducted a functional analysis of these two Toxoplasma PROPPINs. One of them is dispensable for normal in vitro growth, although it may play a role for parasite survival in specific stress conditions or for parasite fitness in the host, through a canonical autophagy-related function. The other, however, seems important for parasite viability in normal growth conditions and could be primarily involved in a non-canonical function. These divergent roles for two proteins from the same family illustrate the functional versatility of the autophagy-related machinery in Toxoplasma.

Pathogenic mycobacteria produce a wide array of lipids which participate in host cell interactions and virulence. While some of these are conserved across all mycobacteria, others, like glycopeptidolipids (GPL), are restricted to a few species. Mycobacterium abscessus , an emerging rapid-growing pathogen, transitions from a smooth to a virulent rough variant upon the loss of surface GPL. Here, we discovered that M. abscessus and phylogenetically-close species harbor a second GPL-related locus, comprising two adjacent non-ribosomal peptide synthetase genes, MAB_4690c and MAB_4691c . A MAB_4690c deletion mutant (Δ MAB_4690c ) failed to produce a yet undescribed lipid, designated GL8P for glycosylated lipooctapeptide, sharing an acylated octapeptide core adorned by mono or di- O -rhamnosyl substituents. Δ MAB_4690c exhibited impaired uptake and survival in THP-1 cells and was attenuated in mice. Importantly, GL8P elicited a strong humoral response in patients infected with M. abscessus . These results highlight the role of GL8P in the pathophysiology of infection by rough M . abscessus and suggest its potential as a selective marker for M . abscessus infections.

This paper presents a financial Stackelberg game model with two partially informed risk neutral insiders. Each insider receives a private signal about the stock value and competes with the other insider under a Stackelberg setting. Linear strategies for the game’s participants are considered and normal distributions for the fundamentals are assumed. Based on the Stackelberg game and the Backward Induction theory, the unique linear equilibrium is characterized. The findings reveal that the level of partial information might increase/decrease the insiders’ profits as well as the market parameter in the Stackelberg setting relative to the Cournot setting. Additionally, this paper considers the information sharing scenario between the two insiders competing in this Stackelberg game. The results show that multiple equilibria exist in contrast to the information sharing scenario in the Cournot game where the Nash equilibrium is unique.

ESX type VII secretion systems are complex secretion machineries spanning across the mycobacterial membrane and play an important role in pathogenicity, nutrient uptake and conjugation. We previously reported the role of ESX-4 in modulating Mycobacterium abscessus intracellular survival. The loss of EccB4 was associated with limited secretion of two effector proteins belonging to the WXG-100 family, EsxU and EsxT, and encoded by the esx-4 locus. This prompted us to investigate the function of M . abscessus EsxU and EsxT in vitro and in vivo . Herein, we show that EsxU and EsxT are substrates of ESX-4 and form a stable 1:1 heterodimer that permeabilizes artificial membranes. While expression of esxU and esxT was up-regulated in M . abscessus -infected macrophages, their absence in an esxUT deletion mutant prevented phagosomal membrane disruption while maintaining M . abscessus in an unacidified phagosome. Unexpectedly, the esxUT deletion was associated with a hyper-virulent phenotype, characterised by increased bacterial loads and mortality in mouse and zebrafish infection models. Collectively, these results demonstrate that the presence of EsxU and EsxT dampens survival and persistence of M . abscessus during infection.

This paper examines the impact of different risk attitudes on the financial decisions of two insiders trading in the stock market. We consider a static version of the Kyle (Econometrica 53:1315-1335, 1985) model with two insiders. Insider 1 is risk neutral while insider 2 is risk averse with negative exponential utility. First, we analytically prove the existence of a unique linear equilibrium. Second, we carry out a comparative static analysis with respect to the duopoly case of risk-neutral insiders (Tighe in Three essays on insider trading. Unpublished Ph.D dissertation, University of Illinois at Champaign-Urbana, 1989) and with respect to the duopoly case of risk-averse insiders (Holden and Subrahmanyam in Econ Lett 44:181-190, 1994) models. Our findings reveal that the market depth and the information revelation are higher in Tighe (1989) than in our model. However, compared to Holden and Subrahmanyam (1994), we find that the market depth depends crucially on the degree of risk aversion. Finally, we show that regardless of the degree of risk aversion, the stock price reveals more information in our model than the stock price in Holden and Subrahmanyam (1994).

This study sheds light into the complex process of intracellular lipid accumulation and storage in the survival and persistence of pathogenic mycobacteria, which is of clinical relevance. By identifying the proteins involved in the formation of intrabacterial lipid inclusions and revealing their impact on lipid metabolism, our data may lead to the development of new therapeutic strategies to target and control pathogenic mycobacteria, potentially improving outcomes for patients with mycobacterial infections.

The invasive forms of apicomplexan parasites share a conserved form of gliding motility that powers parasite migration across biological barriers, host cell invasion and egress from infected cells. Previous studies have established that the duration and direction of gliding motility are determined by actin polymerization; however, regulators of actin dynamics in apicomplexans remain poorly characterized. In the absence of a complete ARP2/3 complex, the formin homology 2 domain containing proteins and the accessory protein profilin are presumed to orchestrate actin polymerization during host cell invasion. Here, we have undertaken the biochemical and functional characterization of two Toxoplasma gondii formins and established that they act in concert as actin nucleators during invasion. The importance of TgFRM1 for parasite motility has been assessed by conditional gene disruption. The contribution of each formin individually and jointly was revealed by an approach based upon the expression of dominant mutants with modified FH2 domains impaired in actin binding but still able to dimerize with their respective endogenous formin. These mutated FH2 domains were fused to the ligand-controlled destabilization domain (DD-FKBP) to achieve conditional expression. This strategy proved unique in identifying the non-redundant and critical roles of both formins in invasion. These findings provide new insights into how controlled actin polymerization drives the directional movement required for productive penetration of parasites into host cells.

Type VII secretion systems participate in protein export, virulence, conjugation, and metabolic regulation. Five subtypes (ESX-1 to ESX-5) exist, each with specific roles and well-characterized secretion profiles in various mycobacterial species. Mycobacterium abscessus , encodes only ESX-3 and ESX-4. Here, single and double M. abscessus mutants lacking the main ATPases EccC3 and EccC4 were used to define ESX-3 and ESX-4 contributions to substrate secretion and virulence. Our results demonstrate that EsxG/H secretion depends entirely on ESX-3, whereas both ESX-3 and ESX-4 secrete EsxU/T. Furthermore, two newly identified PE/PPE substrates (MAB_0046/MAB_0047) require ESX-3 for secretion. Functional complementation restored secretion and revealed subpolar localization of these systems. Macrophage infections showed that ESX-3 and ESX-4 contribute to bacterial internalization, phagosomal escape, and intracellular survival. In mice, infections with eccC3- and/or eccC4 -deletion mutants resulted in complete survival and reduced bacterial loads in the lungs. These findings demonstrate that both ESX systems drive M. abscessus pathogenicity. Investigation of ESX-3 and ESX-4 secretion systems in Mycobacterium abscessus reveals their crucial role in substrate secretion, macrophage infection, and in vivo pathogenicity, highlighting their role in mycobacterial survival and host interactions.