Diverse Gut Pathogens Exploit the Host Engulfment Pathway via a Conserved Mechanism.

Macrophages clear infections by engulfing and digesting pathogens within phagolysosomes. Pathogens escape this fate by engaging in a molecular arms race; they use WxxxE motif-containing effector proteins to subvert the host cells they invade and seek refuge within protective vacuoles. Here we define the host component of the molecular arms race as an evolutionarily conserved polar hotspot on the PH-domain of ELMO1 (Engulfment and Cell Motility1), which is targeted by diverse WxxxE-effectors. Using homology modeling and site-directed mutagenesis, we show that a lysine triad within the patch directly binds all WxxxE-effectors tested: SifA (Salmonella), IpgB1 and IpgB2 (Shigella), and Map (enteropathogenic E. coli). Using an integrated SifA-host protein-protein interaction (PPI) network, in-silico network perturbation, and functional studies we show that the major consequences of preventing SifA-ELMO1 interaction are reduced Rac1 activity and microbial invasion. That multiple effectors of diverse structure, function, and sequence bind the same hotpot on ELMO1 suggests that the WxxxE-effector(s)-ELMO1 interface is a convergence point of intrusion detection and/or host vulnerability. We conclude that the interface may represent the fault line in co-evolved molecular adaptations between pathogens and the host and its disruption may serve as a therapeutic strategy.

Adult student perspectives toward housing during COVID-19.

Precarious housing conditions are on the rise in many developing economies, which has resulted in increasing segmentation between population groups with different socioeconomic backgrounds, and in differentiated access to life chances. With the onset of the COVID-19 pandemic, and its subsequent lockdowns, the relation between learning and housing conditions has become crucial for understanding the adult student's learning experience and well-being. However, knowledge about this relation is limited. This study employs the concept of dwelling to investigate how housing-related precarities may impact upon experiences of students during COVID-19 induced stay-at-home orders. The study draws on fifteen in-depth interviews and a Zoom Video Conferencing (ZVC)-aided focus group in the Ashaiman Municipality in Ghana, to explore students' perspectives on precarious housing conditions, well-being and learning. Findings reveal that experiences of precarious housing conditions can be complicated and compromised in diverse ways related to quality learning environment, financial, and personal well-being. Through ZVC-aided focus groups, participants defined housing suitable for learning - not purely in academic terms but in relation to housing characteristics, the neighbourhood environment, the built environment, and the social relations of learning. The study finds that students perceive an array of economic, social and geographic barriers to learning and that these perspectives deserve attention in adult student housing policy debate.

Noncanonical FK506-binding protein BDBT binds DBT to enhance its circadian function and forms foci at night.

The kinase DOUBLETIME is a master regulator of the Drosophila circadian clock, yet the mechanisms regulating its activity remain unclear. A proteomic analysis of DOUBLETIME interactors led to the identification of an unstudied protein designated CG17282. RNAi-mediated knockdown of CG17282 produced behavioral arrhythmicity and long periods and high levels of hypophosphorylated nuclear PERIOD and phosphorylated DOUBLETIME. Overexpression of DOUBLETIME in flies suppresses these phenotypes and overexpression of CG17282 in S2 cells enhances DOUBLETIME-dependent PERIOD degradation, indicating that CG17282 stimulates DOUBLETIME's circadian function. In photoreceptors, CG17282 accumulates rhythmically in PERIOD- and DOUBLETIME-dependent cytosolic foci. Finally, structural analyses demonstrated CG17282 is a noncanonical FK506-binding protein with an inactive peptide prolyl-isomerase domain that binds DOUBLETIME and tetratricopeptide repeats that may promote assembly of larger protein complexes. We have named CG17282 BRIDE OF DOUBLETIME and established it as a mediator of DOUBLETIME's effects on PERIOD, most likely in cytosolic foci that regulate PERIOD nuclear accumulation.

Receptor protein tyrosine phosphatases and cancer: new insights from structural biology.

There is general agreement that many cancers are associated with aberrant phosphotyrosine signaling, which can be caused by the inappropriate activities of tyrosine kinases or tyrosine phosphatases. Furthermore, incorrect activation of signaling pathways has been often linked to changes in adhesion events mediated by cell surface receptors. Among these receptors, receptor protein tyrosine phosphatases (RPTPs) both antagonize tyrosine kinases as well as engage extracellular ligands. A recent wealth of data on this intriguing family indicates that its members can fulfill either tumor suppressing or oncogenic roles. The interpretation of these results at a molecular level has been greatly facilitated by the recent availability of structural information on the extra- and intracellular regions of RPTPs. These structures provide a molecular framework to understand how alterations in extracellular interactions can inactivate RPTPs in cancers or why the overexpression of certain RPTPs may also participate in tumor progression.