Coarse-Grained and Atomistic MD Simulations of RNA and DNA Folding

Although the main features of the protein folding problem are coming into clearer focus, the microscopic viewpoint of nucleic acid folding mechanisms is only just beginning to be addressed. Experiments, theory, and simulations are pointing to complex thermodynamic and kinetic mechanisms. As is the case for proteins, molecular dynamics (MD) simulations continue to be indispensable tools for providing a molecular basis for nucleic acid folding mechanisms. In this review, we provide an overview of biomolecular folding mechanisms focusing on nucleic acids. We outline the important interactions that are likely to be the main determinants of nucleic acid folding energy landscapes. We discuss recent MD simulation studies of empirical force field and Go-type MD simulations of RNA and DNA folding mechanisms to outline recent successes and the theoretical and computational challenges that lie ahead.     

Structural Analysis of the Black-Legged Tick Saliva Protein Salp15

Salp15 is one of the proteins in the saliva of the tick Ixodes scapularis. Together with other biomolecules injected into the mammalian host at the biting site, it helps the tick to sustain its blood meal for days. Salp15 interferes with the cellular immune response of the mammalian host by inhibiting the activation of CD4⁺ T-lymphocytes. This function is co-opted by pathogens that use the tick as a vector and invade the host when the tick bites, such as Borrelia burgdorferi, the causative agent of Lyme borreliosis. Because of the immunity-suppressing role of Salp15, it has been proposed as a candidate for therapeutic applications in disorders of the immune system. The protein is produced as a 135-residue long polypeptide and secreted without its N-terminal signal 1–21 sequence. Detailed structural studies on Salp15 are lacking because of the difficulty in producing large amounts of the folded protein. We report the production of Salp15 and its structural analysis by NMR. The protein is monomeric and contains a flexible N-terminal region followed by a folded domain with mixed α + β secondary structures. Our results are consistent with a three-dimensional structural model derived from AlphaFold, which predicts the formation of three disulfide bridges and a free C-terminal cysteine.     

Aquaporins Are One of the Critical Factors in the Disruption of the Skin Barrier in Inflammatory Skin Diseases

The skin is the largest organ of the human body, serving as an effective mechanical barrier between the internal milieu and the external environment. The skin is widely considered the first-line defence of the body, with an essential function in rejecting pathogens and preventing mechanical, chemical, and physical damages. Keratinocytes are the predominant cells of the outer skin layer, the epidermis, which acts as a mechanical and water-permeability barrier. The epidermis is a permanently renewed tissue where undifferentiated keratinocytes located at the basal layer proliferate and migrate to the overlying layers. During this migration process, keratinocytes undertake a differentiation program known as keratinization process. Dysregulation of this differentiation process can result in a series of skin disorders. In this context, aquaporins (AQPs), a family of membrane channel proteins allowing the movement of water and small neutral solutes, are emerging as important players in skin physiology and skin diseases. Here, we review the role of AQPs in skin keratinization, hydration, keratinocytes proliferation, water retention, barrier repair, wound healing, and immune response activation. We also discuss the dysregulated involvement of AQPs in some common inflammatory dermatological diseases characterised by skin barrier disruption.     

Design and Characterization of Myristoylated and Non-Myristoylated Peptides Effective against Candida spp. Clinical Isolates

The increasing resistance of fungi to antibiotics is a severe challenge in public health, and newly effective drugs are required. Promising potential medications are lipopeptides, linear antimicrobial peptides (AMPs) conjugated to a lipid tail, usually at the N-terminus. In this paper, we investigated the in vitro and in vivo antifungal activity of three short myristoylated and non-myristoylated peptides derived from a mutant of the AMP Chionodracine. We determined their interaction with anionic and zwitterionic membrane-mimicking vesicles and their structure during this interaction. We then investigated their cytotoxic and hemolytic activity against mammalian cells. Lipidated peptides showed a broad spectrum of activity against a relevant panel of pathogen fungi belonging to Candida spp., including the multidrug-resistant C. auris. The antifungal activity was also observed vs. biofilms of C. albicans, C. tropicalis, and C. auris. Finally, a pilot efficacy study was conducted on the in vivo model consisting of Galleria mellonella larvae. Treatment with the most-promising myristoylated peptide was effective in counteracting the infection from C. auris and C. albicans and the death of the larvae. Therefore, this myristoylated peptide is a potential candidate to develop antifungal agents against human fungal pathogens.     

Monitoring the bacterial population dynamics during fermentation of artisanal Argentinean sausages

The dynamics of the microbial community responsible for the artisanal fermentation of dry sausage produced in Argentina was investigated by using classical and molecular approaches. The combined use of RAPD analysis with primers M13, XD9, RAPD1 and RAPD2 and 16S rDNA sequencing were applied to the identification and intraspecific differentiation of 100 strains of lactobacilli and Micrococcaceae. DGGE analysis was used to monitor the dynamic changes in population after total microbial DNA was directly extracted from sausages and subjected to PCR using V3f (GC), Bact-0124f-GC and Univ-0515r primers. The sequence analysis of 16S rDNA of the dominant species was also carried out. Lactobacillus sakei and Lactobacillus plantarum were the dominant lactic acid organisms during the fermentation while Staphylococcus saprophyticus represented the dominant species of Micrococcaceae. It was demonstrated that the ripening process of Argentinean artisanal fermented sausage is driven by a limited number of Lactobacillus and Staphylococcus strains selected from environmental microbiota by the ability to best compete under the prevailing conditions of the ecological niche. The identification of dominant communities present in this artisanal fermented sausage can help in the selection of starter cultures consisting in well adapted strains to the particular production technology.     

Achieving the Sustainable Development Goals: improving water services in cities affected by extreme weather events

Abstract

This article discusses how key risks from extreme weather events might affect progress towards meeting Sustainable Development Goals 6 and 11 in cities in developing countries. It outlines the magnitude of the existing shortfall in safe water and sanitation services, and how climate change will exacerbate existing problems. It argues that the performance of many governments thus far has lacked urgency and purpose. Unless governments in particular become more committed, with redoubled effort, the goals are unlikely to be achieved.     

Solving constrained optimization problems with a hybrid particle swarm optimization algorithm

This article presents a particle swarm optimization algorithm for solving general constrained optimization problems. The proposed approach introduces different methods to update the particle's information, as well as the use of a double population and a special shake mechanism designed to avoid premature convergence. It also incorporates a simple constraint-handling technique. Twenty-four constrained optimization problems commonly adopted in the evolutionary optimization literature, as well as some structural optimization problems are adopted to validate the proposed approach. The results obtained by the proposed approach are compared with respect to those generated by algorithms representative of the state of the art in the area.     

Quantifying water quality and flow in multi-branched urban estuaries for a rainfall event with mass balance method

In this study, field observations were conducted after a heavy rainfall event in the Sumida and Shakujii rivers in Tokyo, Japan. The flow dynamics and fluxes of salt, suspended sediment (SS), and dissolved oxygen (DO) were investigated with the mass balance method. The fractions of fresh water and saltwater in seaward and landward flows were separated. The maximum salt flux in the Shakujii River was 53.8 kg/s during the flood tide, and those in the Sumida River were 680.3 kg/s at the upstream station and 703.7 kg/s at the downstream station. The trends of SS and DO fluxes were similar in both rivers. In the Shakujii River, the highest SS (3.1 kg/s) and DO (0.4 kg/s) fluxes appeared during the flood tide after rainfall. In the Sumida River, the maximum SS fluxes (6.1 and 6.3 kg/s at the upstream and downstream stations, respectively) and DO fluxes (1.15 and 1.21 kg/s at the upstream and downstream stations, respectively) appeared during the ebb tide. The mass balance method was used to estimate discharge, salinity, SS concentration, and DO concentration at a station with missing data. The results show that the estimated salinity and SS concentration had a significant correlation with the on-site observations, with correlation coefficients (R) of 0.950 and 0.835, respectively, but not for DO concentration (R = 0.638). The disparity between the computed and measured data may be explained by the differences in velocity, salinity, topography, sedimentation, and the presence of organic matter. The analysis based on the advective salt transport components found a lower salt flux per unit width in the Shakujii River (0.36 kg/(m·s)) in comparison with that in the Sumida River (2.88 kg/(m·s)). This indicates a higher probability for salt retention in the Shakujii River.     

An assessment of the Spanish national hydrological plan

The paper is a comprehensive review of the Spanish National Hydrological Plan, which proposes to transfer water from the lower part of the Ebro River up to the Levante basins, around 912 km away. The National Hydrological Plan is a conventional, static plan, which focuses primarily on supply management. The plan is based on the explicit assumption that the world will change only incrementally during its entire economic life of 100-200 years. The analysis indicates that much of the increased water demands forecasted are unlikely to materialize due to increasing emphasis on demand management practices, major structural changes in the agricultural sector that will occur by 2020 and the requirements of the Water Directive of the European Union, which must be fulfilled by 2010. Even now, the cost per cubic metre of water delivered at the end of the transfer is nearly twice the cost of desalinated water. The National Hydrological Plan in its present form cannot be justified for economic, environmental and social reasons. In addition, the plan will not be necessary if demand management practices are implemented.     

Drop-in replacement of R22 in heat pumps used for district heating — influence of equipment and property limitations

In Swedish district heating systems several large (25 MW) turbo-compressor driven heat pumps using R22 are installed. The only commercially available alternative is R134a, but its use could decrease the heating capacity by 35%. In this paper a method for finding the best working fluid for a specific heat pump plant is presented, and applied to a district heating plant. First, a screening is made among almost 2000 mixtures, using criteria such as condenser pressure, Mach number and temperature glide. Simulations of the plant are then made to investigate the change in heating capacity and COP when using a mixture instead of R134a. The results show that there are mixtures that can offer a substantially higher heating capacity than R134a, but there is a decrease in COP. The importance of considering the limiting parameters of the heat pump, such as maximum volume flow to each compressor stage and minimum evaporator pressure, is shown.