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Abstract Cell stiffness is regulated by dynamic interaction between ras-related C3 botulinum toxin substrate 1 (Rac1) and p21 protein-activated kinase 1 (PAK1) proteins, besides other biochemical and molecular regulators. In this study, we investigated how the Placental Growth Factor (PlGF) changes endometrial mechanics by modifying the actin cytoskeleton at the maternal interface. We explored the global effects of PlGF in endometrial stromal cells (EnSCs) using the concerted approach of proteomics, atomic force microscopy (AFM), and electrical impedance spectroscopy (EIS). Proteomic analysis shows PlGF upregulated RhoGTPases activating proteins and extracellular matrix organization-associated proteins in EnSCs. Rac1 and PAK1 transcript levels, activity, and actin polymerization were significantly increased with PlGF treatment. AFM further revealed an increase in cell stiffness with PlGF treatment. The additive effect of PlGF on actin polymerization was suppressed with siRNA-mediated inhibition of Rac1, PAK1, and WAVE2. Interestingly, the increase in cell stiffness by PlGF treatment was pharmacologically reversed with pravastatin, resulting in improved trophoblast cell invasion. Taken together, aberrant PlGF levels in the endometrium can contribute to an altered pre-pregnancy maternal microenvironment and offer a unifying explanation for the pathological changes observed in conditions such as pre-eclampsia (PE).

ABSTRACTEscherichia coli is a highly versatile microorganism with a unique ability to survive and persist in varied niches of the human and animal hosts and the environment. While commensal strains of E. coli play a crucial role in preserving and maintaining the balance and function of their community within the gut microflora, pathogenic strains are often implicated in a wide range of infections and outbreaks, posing a serious threat to public health systems. With the increasing burden of highly virulent and antimicrobial-resistant E. coli infections, it is imperative to understand the host-defense mechanisms of bacteria from all possible dimensions. Mobile genetic elements (MGE)-mediated acquisition of genetic material, chromosomal reduction, and genome optimization are three important events that play a significant role in bacterial evolution and enable them to survive in diverse environmental niches. Toxin-antitoxin (TA) systems are genetic elements that help in the maintenance of MGEs and are often associated with stress response phenotypes, including antimicrobial resistance. In this study, large-scale comparative genomics of 950 genomes spanning 19 different sequence types (STs) (eight phylogroups) revealed ST-wide prevalence patterns of TA systems with a median of 23 toxin groups per strain. Our analyses revealed significant genomic reduction in the members of phylogroup B2 (ST131, ST95, ST73, ST12, and ST127) and phylogroup C (ST410) as evident from a diminished toxin repertoire amidst abundant orphan antitoxins. Moreover, our observations also enabled crucial insights into the copy number of toxin groups, the genetic organization of TA operons, and their association with other genetic coordinates (antimicrobial resistance encoding genes/virulence genes/mobile genetic elements). By unraveling the association of the genetic coordinates/STs with the toxin groups, this study significantly boosts our understanding of the functional implications of TA systems in different evolutionary contexts entailing pathogenic Escherichia.IMPORTANCELarge-scale genomic studies of E. coli provide an invaluable opportunity to understand how genomic fine-tuning contributes to the transition of bacterial lifestyle from being commensals to mutualists or pathogens. Within this context, through machine learning-based studies, it appears that TA systems play an important role in the classification of high-risk clonal lineages and could be attributed to their epidemiological success. Due to these profound indications and assumptions, we attempted to provide unique insights into the ordered world of TA systems at the population level by investigating the diversity and evolutionary patterns of TA genes across 19 different STs of E. coli. Further in-depth analysis of ST-specific TA structures and associated genetic coordinates holds the potential to elucidate the functional implications of TA systems in bacterial cell survival and persistence, by and large.

Salmonella enterica (S. enterica) has infected humans for a long time, but its evolutionary history and geographic spread across Eurasia is still poorly understood. Here, we screened for pathogen DNA in 14 ancient individuals from the Bronze Age Quanergou cemetery (XBQ), Xinjiang, China. In 6 individuals we detected S. enterica. We reconstructed S. enterica genomes from those individuals, which form a previously undetected phylogenetic branch basal to Paratyphi C, Typhisuis and Choleraesuis-the so-called Para C lineage. Based on pseudogene frequency, our analysis suggests that the ancient S. enterica strains were not host adapted. One genome, however, harbors the Salmonella pathogenicity island 7 (SPI-7), which is thought to be involved in (para)typhoid disease in humans. This offers first evidence that SPI-7 was acquired prior to the emergence of human-adapted Paratyphi C around 1,000 years ago. Altogether, our results show that Salmonella enterica infected humans in Eastern Eurasia at least 3,000 years ago, and provide the first ancient DNA evidence for the spread of a pathogen along the Proto-Silk Road.

The mechanisms behind CO2 dependency in non-autotrophic bacterial isolates are unclear. Here the authors show that the Staphylococcus aureus mpsAB operon is crucial for growth at atmospheric CO2 levels, and provide evidence indicating that MpsAB represents a bicarbonate concentrating system.

Treponema pallidum infections occur worldwide causing, among other diseases, syphilis and yaws. In particular sexually transmitted syphilis is regarded as a re-emerging infectious disease with millions of new infections annually. Here we present three historic T. pallidum genomes (two from T. pallidum ssp. pallidum and one from T. pallidum ssp. pertenue) that have been reconstructed from skeletons recovered from the Convent of Santa Isabel in Mexico City, operational between the 17th and 19th century. Our analyses indicate that different T. pallidum subspecies caused similar diagnostic presentations that are normally associated with syphilis in infants, and potential evidence of a congenital infection of T. pallidum ssp. pertenue, the causative agent of yaws. This first reconstruction of T. pallidum genomes from archaeological material opens the possibility of studying its evolutionary history at a resolution previously assumed to be out of reach.

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