Role of miRNA polymorphism in recurrent pregnancy loss: a systematic review and meta-analysis

There are a plethora of publications on the role of miRNA gene polymorphism and its association with recurrent pregnancy loss (RPL), but a lack of uniformity in the studies available due to the variable subject population, heterogeneity and contrary results of significance. Rigorous data mining was done through PubMed, SCOPUS, Cochrane library, Elsevier and Google Scholar to extract the studies of interest published until June 2021. A total of eight SNPs of miRNAs have been included, where ≥2 studies per SNPs were available. Analysis was done on the basis of pooled odds ratios and 95% CI. This is the first meta-analysis on miRNA SNPs in RPL that suggests that rs11614913, rs3746444 and rs2292832 biomarkers may decrease the risk of RPL under different genetic models.

The Use of Drosophila to Understand Psychostimulant Responses

The addictive properties of psychostimulants such as cocaine, amphetamine, methamphetamine, and methylphenidate are based on their ability to increase dopaminergic neurotransmission in the reward system. While cocaine and methamphetamine are predominately used recreationally, amphetamine and methylphenidate also work as effective therapeutics to treat symptoms of disorders including attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Although both the addictive properties of psychostimulant drugs and their therapeutic efficacy are influenced by genetic variation, very few genes that regulate these processes in humans have been identified. This is largely due to population heterogeneity which entails a requirement for large samples. Drosophila melanogaster exhibits similar psychostimulant responses to humans, a high degree of gene conservation, and allow performance of behavioral assays in a large population. Additionally, amphetamine and methylphenidate reduce impairments in fly models of ADHD-like behavior. Therefore, Drosophila represents an ideal translational model organism to tackle the genetic components underlying the effects of psychostimulants. Here, we break down the many assays that reliably quantify the effects of cocaine, amphetamine, methamphetamine, and methylphenidate in Drosophila. We also discuss how Drosophila is an efficient and cost-effective model organism for identifying novel candidate genes and molecular mechanisms involved in the behavioral responses to psychostimulant drugs.

Dissecting the dominant hot spring microbial populations based on community-wide sampling at single-cell genomic resolution

With advances in DNA sequencing and miniaturized molecular biology workflows, rapid and affordable sequencing of single-cell genomes has become a reality. Compared to 16S rRNA gene surveys and shotgun metagenomics, large-scale application of single-cell genomics to whole microbial communities provides an integrated snapshot of community composition and function, directly links mobile elements to their hosts, and enables analysis of population heterogeneity of the dominant community members. To that end, we sequenced nearly 500 single-cell genomes from a low diversity hot spring sediment sample from Dewar Creek, British Columbia, and compared this approach to 16S rRNA gene amplicon and shotgun metagenomics applied to the same sample. We found that the broad taxonomic profiles were similar across the three sequencing approaches, though several lineages were missing from the 16S rRNA gene amplicon dataset, likely the result of primer mismatches. At the functional level, we detected a large array of mobile genetic elements present in the single-cell genomes but absent from the corresponding same species metagenome-assembled genomes. Moreover, we performed a single-cell population genomic analysis of the three most abundant community members, revealing differences in population structure based on mutation and recombination profiles. While the average pairwise nucleotide identities were similar across the dominant species-level lineages, we observed differences in the extent of recombination between these dominant populations. Most intriguingly, the creek’s Hydrogenobacter sp. population appeared to be so recombinogenic that it more closely resembled a sexual species than a clonally evolving microbe. Together, this work demonstrates that a randomized single-cell approach can be useful for the exploration of previously uncultivated microbes from community composition to population structure.

Heterogeneous Pancreatic Stellate Cells Are Powerful Contributors to the Malignant Progression of Pancreatic Cancer

Pancreatic cancer is associated with highly malignant tumors and poor prognosis due to strong therapeutic resistance. Accumulating evidence shows that activated pancreatic stellate cells (PSC) play an important role in the malignant progression of pancreatic cancer. In recent years, the rapid development of single-cell sequencing technology has facilitated the analysis of PSC population heterogeneity, allowing for the elucidation of the relationship between different subsets of cells with tumor development and therapeutic resistance. Researchers have identified two spatially separated, functionally complementary, and reversible subtypes, namely myofibroblastic and inflammatory PSC. Myofibroblastic PSC produce large amounts of pro-fibroproliferative collagen fibers, whereas inflammatory PSC express large amounts of inflammatory cytokines. These distinct cell subtypes cooperate to create a microenvironment suitable for cancer cell survival. Therefore, further understanding of the differentiation of PSC and their distinct functions will provide insight into more effective treatment options for pancreatic cancer patients.

Influence of Ribavirin on Mumps Virus Population Diversity

Frequent mumps outbreaks in vaccinated populations and the occurrence of neurological complications (e.g., aseptic meningitis or encephalitis) in patients with mumps indicate the need for the development of more efficient vaccines as well as specific antiviral therapies. RNA viruses are genetically highly heterogeneous populations that exist on the edge of an error threshold, such that additional increases in mutational burden can lead to extinction of the virus population. Deliberate modulation of their natural mutation rate is being exploited as an antiviral strategy and a possibility for rational vaccine design. The aim of this study was to examine the ability of ribavirin, a broad-spectrum antiviral agent, to introduce mutations in the mumps virus (MuV) genome and to investigate if resistance develops during long-term in vitro exposure to ribavirin. An increase in MuV population heterogeneity in the presence of ribavirin has been observed after one passage in cell culture, as well as a bias toward C-to-U and G-to-A transitions, which have previously been defined as ribavirin-related. At higher ribavirin concentration, MuV loses its infectivity during serial passaging and does not recover. At low ribavirin concentration, serial passaging leads to a more significant increase in population diversity and a stronger bias towards ribavirin-related transitions, independently of viral strain or cell culture. In these conditions, the virus retains its initial growth capacity, without development of resistance at a whole-virus population level.

Dietary Phytoestrogens and Their Metabolites as Epigenetic Modulators with Impact on Human Health

The impact of dietary phytoestrogens on human health has been a topic of continuous debate since their discovery. Nowadays, based on their presumptive beneficial effects, the amount of phytoestrogens consumed in the daily diet has increased considerably worldwide. Thus, there is a growing need for scientific data regarding their mode of action in the human body. Recently, new insights of phytoestrogens’ bioavailability and metabolism have demonstrated an inter-and intra-population heterogeneity of final metabolites’ production. In addition, the phytoestrogens may have the ability to modulate epigenetic mechanisms that control gene expression. This review highlights the complexity and particularity of the metabolism of each class of phytoestrogens, pointing out the diversity of their bioactive gut metabolites. Futhermore, it presents emerging scientific data which suggest that, among well-known genistein and resveratrol, other phytoestrogens and their gut metabolites can act as epigenetic modulators with a possible impact on human health. The interconnection of dietary phytoestrogens’ consumption with gut microbiota composition, epigenome and related preventive mechanisms is discussed. The current challenges and future perspectives in designing relevant research directions to explore the potential health benefits of dietary phytoestrogens are also explored.

Bayesian inference on the number of recurrent events: A joint model of recurrence and survival

The number of recurrent events before a terminating event is often of interest. For instance, death terminates an individual’s process of rehospitalizations and the number of rehospitalizations is an important indicator of economic cost. We propose a model in which the number of recurrences before termination is a random variable of interest, enabling inference and prediction on it. Then, conditionally on this number, we specify a joint distribution for recurrence and survival. This novel conditional approach induces dependence between recurrence and survival, which is often present, for instance, due to frailty that affects both. Additional dependence between recurrence and survival is introduced by the specification of a joint distribution on their respective frailty terms. Moreover, through the introduction of an autoregressive model, our approach is able to capture the temporal dependence in the recurrent events trajectory. A non-parametric random effects distribution for the frailty terms accommodates population heterogeneity and allows for data-driven clustering of the subjects. A tailored Gibbs sampler involving reversible jump and slice sampling steps implements posterior inference. We illustrate our model on colorectal cancer data, compare its performance with existing approaches and provide appropriate inference on the number of recurrent events.

Evasion of Toll-like Receptor Recognition by Escherichia coli is mediated via Population Level Regulation of Flagellin Production

Uropathogenic Escherichia coli (UPEC) is a major cause of urinary tract infections. Analysis of the innate immune response in immortalised urothelial cells suggests that the bacterial flagellar subunit, flagellin, is key in inducing host defences. A panel of 39 clinical uro-associated Escherichia coli isolates recovered from either asymptomatic bacteruria (ASB), cystitis or pyelonephritis patients, were characterised for motility and their ability to induce an innate response in urothelial cells stably transfected with a NFκB luciferase reporter. Twenty-four isolates (60%) were identified as motile with strains recovered from cystitis patients exhibiting a bipolar motility distribution pattern (P < 0.005) and associated with a 2-5 fold increase in NFκB signalling. Although two isolates were associated with swarm sizes of >7 cm and NFκB activities of >30 fold (P = 0.029), data overall suggested bacterial motility and the NFκB signalling response were not directly correlated. To explore whether the signalling response reflected antigenic variation flagellin was purified from 11 different isolates and the urothelial cell challenges repeated. Purified flagellin filaments generated comparable (30.4±1.8 to 46.1±2.5 fold, P = NS) NFκB signalling responses, irrespective of either the source of the isolate or H-serotype. These data argued against any variability between isolates being related to flagellin itself. To determine the roles, if any, of flagellar abundance in inducing these responses flagellar hook numbers of a range of cystitis and ABU isolates were quantified using a plasmid encoded flagellar hook gene flgEA240C. Foci data suggested isolates were averaging between 1 and 2 flagella per cell, while only 10 to 60% each isolates population exhibited foci. These data suggested selective pressures exist in the urinary tract that allow uro-associated E. coli strains to maintain motility exploiting population heterogeneity to prevent host TLR5 recognition.

Wafer-Scale Patterning of Protein Templates for Hydrogel Fabrication

Human-induced pluripotent stem cell-derived cardiomyocytes are a potentially unlimited cell source and promising patient-specific in vitro model of cardiac diseases. Yet, these cells are limited by immaturity and population heterogeneity. Current in vitro studies aiming at better understanding of the mechanical and chemical cues in the microenvironment that drive cellular maturation involve deformable materials and precise manipulation of the microenvironment with, for example, micropatterns. Such microenvironment manipulation most often involves microfabrication protocols which are time-consuming, require cleanroom facilities and photolithography expertise. Here, we present a method to increase the scale of the fabrication pipeline, thereby enabling large-batch generation of shelf-stable microenvironment protein templates on glass chips. This decreases fabrication time and allows for more flexibility in the subsequent steps, for example, in tuning the material properties and the selection of extracellular matrix or cell proteins. Further, the fabrication of deformable hydrogels has been optimized for compatibility with these templates, in addition to the templates being able to be used to acquire protein patterns directly on the glass chips. With our approach, we have successfully controlled the shapes of cardiomyocytes seeded on Matrigel-patterned hydrogels.

Stochastic social behavior coupled to COVID-19 dynamics leads to waves, plateaus and an endemic state

It is well recognized that population heterogeneity plays an important role in the spread of epidemics. While individual variations in social activity are often assumed to be persistent, i.e. constant in time, here we discuss the consequences of dynamic heterogeneity. By integrating the stochastic dynamics of social activity into traditional epidemiological models we demonstrate the emergence of a new long timescale governing the epidemic, in broad agreement with empirical data. Our Stochastic Social Activity model captures multiple features of real-life epidemics such as COVID-19, including prolonged plateaus and multiple waves, which are transiently suppressed due to the dynamic nature of social activity. The existence of a long timescale due to the interplay between epidemic and social dynamics provides a unifying picture of how a fast-paced epidemic typically will transition to an endemic state.