Generic Darwinian selection in catalytic protocell assemblies

To satisfy the minimal requirements for life, an information carrying molecular structure must be able to convert resources into building blocks and also be able to adapt to or modify its environment to enhance its own proliferation. Furthermore, new copies of itself must have variable fitness such that evolution is possible. In practical terms, a minimal protocell should be characterized by a strong coupling between its metabolism and genetic subsystem, which is made possible by the container. There is still no general agreement on how such a complex system might have been naturally selected for in a prebiotic environment. However, the historical details are not important for our investigations as they are related to assembling and evolution of protocells in the laboratory. Here, we study three different minimal protocell models of increasing complexity, all of them incorporating the coupling between a 'genetic template', a container and, eventually, a toy metabolism. We show that for any local growth law associated with template self-replication, the overall temporal evolution of all protocell's components follows an exponential growth (efficient or uninhibited autocatalysis). Thus, such a system attains exponential growth through coordinated catalytic growth of its component subsystems, independent of the replication efficiency of the involved subsystems. As exponential growth implies the survival of the fittest in a competitive environment, these results suggest that protocell assemblies could be efficient vehicles in terms of evolving through Darwinian selection.     

Blocking autophagy overcomes resistance to dual histone deacetylase and proteasome inhibition in gynecologic cancer

Histone deacetylase (HDAC) inhibitors and proteasome inhibitors have been approved by the FDA for the treatment of multiple myeloma and lymphoma, respectively, but have not achieved similar activity as single agents in solid tumors. Preclinical studies have demonstrated the activity of the combination of an HDAC inhibitor and a proteasome inhibitor in a variety of tumor models. However, the mechanisms underlying sensitivity and resistance to this combination are not well-understood. This study explores the role of autophagy in adaptive resistance to dual HDAC and proteasome inhibition. Studies focus on ovarian and endometrial gynecologic cancers, two diseases with high mortality and a need for novel treatment approaches. We found that nanomolar concentrations of the proteasome inhibitor ixazomib and HDAC inhibitor romidepsin synergistically induce cell death in the majority of gynecologic cancer cells and patient-derived organoid (PDO) models created using endometrial and ovarian patient tumor tissue. However, some models were not sensitive to this combination, and mechanistic studies implicated autophagy as the main mediator of cell survival in the context of dual HDAC and proteasome inhibition. Whereas the combination of ixazomib and romidepsin reduces autophagy in sensitive gynecologic cancer models, autophagy is induced following drug treatment of resistant cells. Pharmacologic or genetic inhibition of autophagy in resistant cells reverses drug resistance as evidenced by an enhanced anti-tumor response both in vitro and in vivo. Taken together, our findings demonstrate a role for autophagic-mediated cell survival in proteasome inhibitor and HDAC inhibitor-resistant gynecologic cancer cells. These data reveal a new approach to overcome drug resistance by inhibiting the autophagy pathway.Subject terms: Gynaecological cancer, Preclinical research     

Optic Neuritis in Multiple Sclerosis—A Review of Molecular Mechanisms Involved in the Degenerative Process

Multiple sclerosis is a central nervous system inflammatory demyelinating disease with a wide range of clinical symptoms, ocular involvement being frequently marked by the presence of optic neuritis (ON). The emergence and progression of ON in multiple sclerosis is based on various pathophysiological mechanisms, disease progression being secondary to inflammation, demyelination, or axonal degeneration. Early identification of changes associated with axonal degeneration or further investigation of the molecular processes underlying remyelination are current concerns of researchers in the field in view of the associated therapeutic potential. This article aims to review and summarize the scientific literature related to the main molecular mechanisms involved in defining ON as well as to analyze existing data in the literature on remyelination strategies in ON and their impact on long-term prognosis.     

Linguistic evidence supports date for Homeric epics

The Homeric epics are among the greatest masterpieces of literature, but when they were produced is not known with certainty. Here we apply evolutionary‐linguistic phylogenetic statistical methods to differences in Homeric, Modern Greek and ancient Hittite vocabulary items to estimate a date of approximately 710–760 BCE for these great works. Our analysis compared a common set of vocabulary items among the three pairs of languages, recording for each item whether the words in the two languages were cognate – derived from a shared ancestral word – or not. We then used a likelihood‐based Markov chain Monte Carlo procedure to estimate the most probable times in years separating these languages given the percentage of words they shared, combined with knowledge of the rates at which different words change. Our date for the epics is in close agreement with historians' and classicists' beliefs derived from historical and archaeological sources.     

Spatio-temporal insights into microbiology of the freshwater-to-hypersaline,oxic-hypoxic-euxinic waters of Ursu Lake

Ursu Lake is located in the Middle Miocene salt deposit of Central Romania. It is stratified, and the water column has three distinct water masses: an upper freshwater-to-moderately saline stratum (0–3 m), an intermediate stratum exhibiting a steep halocline (3–3.5 m), and a lower hypersaline stratum (4 m and below) that is euxinic (i.e. anoxic and sulphidic). Recent studies have characterized the lake's microbial taxonomy and given rise to intriguing ecological questions. Here, we explore whether the communities are dynamic or stable in relation to taxonomic composition, geochemistry, biophysics, and ecophysiological functions during the annual cycle. We found: (i) seasonally fluctuating, light-dependent communities in the upper layer (≥0.987–0.990 water-activity), a stable but phylogenetically diverse population of heterotrophs in the hypersaline stratum (water activities down to 0.762) and a persistent plate of green sulphur bacteria that connects these two (0.958–0.956 water activity) at 3–3.5 to 4 m; (ii) communities that might be involved in carbon- and sulphur-cycling between and within the lake's three main water masses; (iii) uncultured lineages including Acetothermia (OP1), Cloacimonetes (WWE1), Marinimicrobia (SAR406), Omnitrophicaeota (OP3), Parcubacteria (OD1) and other Candidate Phyla Radiation bacteria, and SR1 in the hypersaline stratum (likely involved in the anaerobic steps of carbon- and sulphur-cycling); and (iv) that species richness and habitat stability are associated with high redox-potentials. Ursu Lake has a unique and complex ecology, at the same time exhibiting dynamic fluctuations and stability, and can be used as a modern analogue for ancient euxinic water bodies and comparator system for other stratified hypersaline systems.     

Adaptive regulation of riboflavin transport in heart: effect of dietary riboflavin deficiency in cardiovascular pathogenesis

Deficiency or defective transport of riboflavin (RF) is known to cause neurological disorders, cataract, cardiovascular anomalies, and various cancers by altering the biochemical pathways. Mechanisms and regulation of RF uptake process is well characterized in the cells of intestine, liver, kidney, and brain origin, while very little is known in the heart. Hence, we aimed to understand the expression and regulation of RF transporters (rRFVT-1 and rRFVT-2) in cardiomyocytes during RF deficiency and also investigated the role of RF in ischemic cardiomyopathy and mitochondrial dysfunction in vivo. Riboflavin uptake assay revealed that RF transport in H9C2 is (1) significantly higher at pH 7.5, (2) independent of Na⁺ and (3) saturable with a Km of 3.746 µM. For in vivo studies, male Wistar rats (110–130 g) were provided riboflavin deficient food containing 0.3 ± 0.05 mg/kg riboflavin for 7 weeks, which resulted in over expression of both RFVTs in mRNA and protein level. RF deprivation resulted in the accumulation of cardiac biomarkers, histopathological abnormalities, and reduced mitochondrial membrane potential which evidenced the key role of RF in the development of cardiovascular pathogenesis. Besides, adaptive regulation of RF transporters upon RF deficiency signifies that RFVTs can be considered as an effective delivery system for drugs against cardiac diseases.     

Qualitative and quantitative characterization of protein-phosphoinositide interactions with liposome-based methods

We characterized phosphoinositide binding of the S. cerevisiae PROPPIN Hsv2 qualitatively with density flotation assays and quantitatively through isothermal titration calorimetry (ITC) measurements using liposomes. We discuss the design of these experiments and show with liposome flotation assays that Hsv2 binds with high specificity to both PtdIns3P and PtdIns(3,5)P₂. We propose liposome flotation assays as a more accurate alternative to the commonly used PIP strips for the characterization of phosphoinositide-binding specificities of proteins. We further quantitatively characterized PtdIns3P binding of Hsv2 with ITC measurements and determined a dissociation constant of 0.67 µM and a stoichiometry of 2:1 for PtdIns3P binding to Hsv2. PtdIns3P is crucial for the biogenesis of autophagosomes and their precursors. Besides the PROPPINs there are other PtdIns3P binding proteins with a link to autophagy, which includes the FYVE-domain containing proteins ZFYVE1/DFCP1 and WDFY3/ALFY and the PX-domain containing proteins Atg20 and Snx4/Atg24. The methods described could be useful tools for the characterization of these and other phosphoinositide-binding proteins.     

Decreased influenza-specific B cell responses in rheumatoid arthritis patients treated with anti-tumor necrosis factor

Introduction

As a group, rheumatoid arthritis (RA) patients exhibit increased risk of infection, and those treated with anti-tumor necrosis factor (TNF) therapy are at further risk. This increased susceptibility may result from a compromised humoral immune response. Therefore, we asked if short-term effector (d5-d10) and memory (1 month or later) B cell responses to antigen were compromised in RA patients treated with anti-TNF therapy.

Methods

Peripheral blood samples were obtained from RA patients, including a subset treated with anti-TNF, and from healthy controls to examine influenza-specific responses following seasonal influenza vaccination. Serum antibody was measured by hemagglutination inhibition assay. The frequency of influenza vaccine-specific antibody secreting cells and memory B cells was measured by EliSpot. Plasmablast (CD19+IgD-CD27hiCD38hi) induction was measured by flow cytometry.

Results

Compared with healthy controls, RA patients treated with anti-TNF exhibited significantly decreased influenza-specific serum antibody and memory B cell responses throughout multiple years of the study. The short-term influenza-specific effector B cell response was also significantly decreased in RA patients treated with anti-TNF as compared with healthy controls, and correlated with decreased influenza-specific memory B cells and serum antibody present at one month following vaccination.

Conclusions

RA patients treated with anti-TNF exhibit a compromised immune response to influenza vaccine, consisting of impaired effector and consequently memory B cell and antibody responses. The results suggest that the increased incidence and severity of infection observed in this patient population could be a consequence of diminished antigen-responsiveness. Therefore, this patient population would likely benefit from repeat vaccination and from vaccines with enhanced immunogenicity.