On Water Arrangements in Right- and Left-Handed DNA Structures.

DNA requires hydration to maintain its structural integrity. Crystallographic analyses have enabled patterns of water arrangements to be visualized. We survey these water motifs in this review, focusing on left- and right-handed duplex and quadruplex DNAs, together with the i-motif. Common patterns of linear spines of water organization in grooves have been identified and are widely prevalent in right-handed duplexes and quadruplexes. By contrast, a left-handed quadruplex has a distinctive wheel of hydration populating the almost completely circular single groove in this structure.

High-resolution structure of the amino acid transporter AdiC reveals insights into the role of water molecules and networks in oligomerization and substrate binding.

BACKGROUND: The L-arginine/agmatine transporter AdiC is part of the arginine-dependent extreme acid resistance system of the bacterium Escherichia coli and its pathogenic varieties such as strain E. coli O157:H7. At the present time, there is a lack of knowledge concerning the role of water molecules and networks for the structure and function of AdiC, and solute transporters in general. RESULTS: The structure of the L-arginine/agmatine transporter AdiC was determined at 1.7 Å resolution by X-ray crystallography. This high resolution allowed for the identification of numerous water molecules buried in the structure. In combination with molecular dynamics (MD) simulations, we demonstrate that water molecules play an important role for stabilizing the protein and key residues, and act as placeholders for atoms of the AdiC substrates L-arginine and agmatine. MD simulations unveiled flexibility and restrained mobility of gating residues W202 and W293, respectively. Furthermore, a water-filled cavity was identified at the dimer interface of AdiC. The two monomers formed bridging interactions through water-mediated hydrogen bonds. The accessibility and presence of water molecules in this cavity was confirmed with MD simulations. Point mutations disrupting the interfacial water network validated the importance of water molecules for dimer stabilization. CONCLUSIONS: This work gives new insights into the role and importance of water molecules in the L-arginine/agmatine transporter AdiC for protein stabilization and substrate-binding site shaping and as placeholders of substrate atoms. Furthermore, and based on the observed flexibility and restrained mobility of gating residues, a mechanistic role of the gate flexibility in the transport cycle was proposed. Finally, we identified a water-filled cavity at the dimeric interface that contributes to the stability of the amino acid transporter oligomer.

Water Networks Repopulate Protein-Ligand Interfaces with Temperature.

High-resolution crystal structures highlight the importance of water networks in protein-ligand interactions. However, as these are typically determined at cryogenic temperature, resulting insights may be structurally precise but not biologically accurate. By collecting 10 matched room-temperature and cryogenic datasets of the biomedical target Hsp90α, we identified changes in water networks that impact protein conformations at the ligand binding interface. Water repositioning with temperature repopulates protein ensembles and ligand interactions. We introduce Flipper conformational barcodes to identify temperature-sensitive regions in electron density maps. This revealed that temperature-responsive states coincide with ligand-responsive regions and capture unique binding signatures that disappear upon cryo-cooling. Our results have implications for discovering Hsp90 selective ligands, and, more generally, for the utility of hidden protein and water conformations in drug discovery.

Impact of lockdown on the microbiological status of the hospital water network during COVID-19 pandemic.

The COVID-19 pandemic started in China in early December 2019, and quickly spread around the world. The epidemic gradually started in Italy at the end of February 2020, and by May 31, 2020, 232,664 cases and 33,340 deaths were confirmed. As a result of this pandemic, the Italian Ministerial Decree issued on March 11, 2020, enforced lockdown; therefore, many social, recreational, and cultural centers remained closed for months. In Apulia (southern Italy), all non-urgent hospital activities were suspended, and some wards were closed, with a consequent reduction in the use of the water network and the formation of stagnant water. This situation could enhance the risk of exposure of people to waterborne diseases, including legionellosis. The purpose of this study was to monitor the microbiological quality of the water network (coliforms, E. coli, Enterococci, P. aeruginosa, and Legionella) in three wards (A, B and C) of a large COVID-19 regional hospital, closed for three months due to the COVID-19 emergency. Our study revealed that all three wards' water network showed higher contamination by Legionella pneumophila sg 1 and sg 6 at T1 (after lockdown) compared to the period before the lockdown (T0). In particular, ward A at T1 showed a median value = 5600 CFU/L (range 0-91,000 CFU/L) vs T0, median value = 75 CFU/L (range 0-5000 CFU/L) (p-value = 0.014); ward B at T1 showed a median value = 200 CFU/L (range 0-4200 CFU/L) vs T0, median value = 0 CFU/L (range 0-300 CFU/L) (p-value = 0.016) and ward C at T1 showed a median value = 175 CFU/L (range 0-22,000 CFU/L) vs T0, median value = 0 CFU/L (range 0-340 CFU/L) (p-value < 0.001). In addition, a statistically significant difference was detected in ward B between the number of positive water samples at T0 vs T1 for L. pneumophila sg 1 and sg 6 (24% vs 80% p-value < 0.001) and for coliforms (0% vs 64% p-value < 0.001). Moreover, a median value of coliform load resulted 3 CFU/100 ml (range 0-14 CFU/100 ml) at T1, showing a statistically significant increase versus T0 (0 CFU/100 ml) (p-value < 0.001). Our results highlight the need to implement a water safety plan that includes staff training and a more rigorous environmental microbiological surveillance in all hospitals before occupying a closed ward for a longer than one week, according to national and international guidelines.

Quantifying the Computational Efficiency of Compressive Sensing in Smart Water Network Infrastructures.

Monitoring contemporary water distribution networks (WDN) relies increasingly on smart metering technologies and wireless sensor network infrastructures. Smart meters and sensor nodes are deployed to capture and transfer information from the WDN to a control center for further analysis. Due to difficulties in accessing the water assets, many water utility companies employ battery-powered nodes, which restricts the use of high sampling rates, thus limiting the knowledge we can extract from the recorder data. To mitigate this issue, compressive sensing (CS) has been introduced as a powerful framework for reducing dramatically the required bandwidth and storage resources, without diminishing the meaningful information content. Despite its well-established and mathematically rigorous foundations, most of the focus is given on the algorithmic perspective, while the real benefits of CS in practical scenarios are still underexplored. To address this problem, this work investigates the advantages of a CS-based implementation on real sensing devices utilized in smart water networks, in terms of execution speedup and reduced ener experimental evaluation revealed that a CS-based scheme can reduce compression execution times around 50 % , while achieving significant energy savings compared to lossless compression, by selecting a high compression ratio, without compromising reconstruction fidelity. Most importantly, the above significant savings are achieved by simultaneously enabling a weak encryption of the recorded data without the need for additional encryption hardware or software components.

Pharmacophoric Site Identification and Inhibitor Design for Autotaxin.

Autotaxin (ATX) is a potential drug target that is associated with inflammatory diseases and various cancers. In our previous studies, we have designed several inhibitors targeting ATX using computational and experimental approaches. Here, we have analyzed topological water networks (TWNs) in the binding pocket of ATX. TWN analysis revealed a pharmacophoric site inside the pocket. We designed and synthesized compounds considering the identified pharmacophoric site. Furthermore, we performed biological experiments to determine their ATX inhibitory activities. High potency of the designed compounds supports the predictions of the TWN analysis.

Towards transferable metamodels for water distribution systems with edge-based graph neural networks.

Data-driven metamodels reproduce the input-output mapping of physics-based models while significantly reducing simulation times. Such techniques are widely used in the design, control, and optimization of water distribution systems. Recent research highlights the potential of metamodels based on Graph Neural Networks as they efficiently leverage graph-structured characteristics of water distribution systems. Furthermore, these metamodels possess inductive biases that facilitate generalization to unseen topologies. Transferable metamodels are particularly advantageous for problems that require an efficient evaluation of many alternative layouts or when training data is scarce. However, the transferability of metamodels based on GNNs remains limited, due to the lack of representation of physical processes that occur on edge level, i.e. pipes. To address this limitation, our work introduces Edge-Based Graph Neural Networks, which extend the set of inductive biases and represent link-level processes in more detail than traditional Graph Neural Networks. Such an architecture is theoretically related to the constraints of mass conservation at the junctions. To verify our approach, we test the suitability of the edge-based network to estimate pipe flowrates and nodal pressures emulating steady-state EPANET simulations. We first compare the effectiveness of the metamodels on several benchmark water distribution systems against Graph Neural Networks. Then, we explore transferability by evaluating the performance on unseen systems. For each configuration, we calculate model performance metrics, such as coefficient of determination and speed-up with respect to the original numerical model. Our results show that the proposed method captures the pipe-level physical processes more accurately than node-based models. When tested on unseen water networks with a similar distribution of demands, our model retains a good generalization performance with a coefficient of determination of up to 0.98 for flowrates and up to 0.95 for predicted heads. Further developments could include simultaneous derivation of pressures and flowrates.

Persistent contamination of a hospital hot water network by Legionellapneumophila.

OBJECTIVES: We assessed the contamination with Legionella pneumophila (Lp) of the hot water network (HWN) of a hospital, mapped the risk of contamination, and evaluated the relatedness of isolates. We further validated phenotypically the biological features that could account for the contamination of the network. METHODS: We collected 360 water samples from October 2017 to September 2018 in 36 sampling points of a HWN of a building from a hospital in France. Lp were quantified and identified with culture-based methods and serotyping. Lp concentrations were correlated with water temperature, date and location of isolation. Lp isolates were genotyped by pulsed-field gel electrophoresis and compared to a collection of isolates retrieved in the same HWN two years later, or in other HWN from the same hospital. RESULTS: 207/360 (57.5%) samples were positive with Lp. In the hot water production system, Lp concentration was negatively associated with water temperature. In the distribution system, the risk of recovering Lp decreased when temperature was >55 °C (p < 10-3), the proportion of samples with Lp increased with distance from the production network (p < 10-3), and the risk of finding high loads of Lp increased 7.96 times in summer (p = 0.001). All Lp isolates (n = 135) were of serotype 3, and 134 (99.3%) shared the same pulsotype which is found two years later (Lp G). In vitro competition experiments showed that a 3-day culture of Lp G on agar inhibited the growth of a different pulsotype of Lp (Lp O) contaminating another HWN of the same hospital (p = 0.050). We also found that only Lp G survived to a 24h-incubation in water at 55 °C (p = 0.014). CONCLUSION: We report here a persistent contamination with Lp of a hospital HWN. Lp concentrations were correlated with water temperature, season, and distance from the production system. Such persistent contamination could be due to biotic parameters such as intra-Legionella inhibition and tolerance to high temperature, but also to the non-optimal configuration of the HWN that prevented the maintenance of high temperature and optimal water circulation.

Benchmarking dataset for leak detection and localization in water distribution systems.

This paper presents a dataset with two hundred and eighty sensory measurements for leak detection and localization in water distribution systems. The data were generated via a laboratory-scale water distribution system that included (1) three types of sensors: accelerometer, hydrophone, and dynamic pressure sensor; (2) four leak types: orifice leak, longitudinal and circumferential cracks, gasket leak, and no-leak condition; (3) two network topologies: looped and branched; and (4) six background conditions with different noise and demand variations. Each measurement was 30 s long, and the measurement frequencies were 51.2 kHz for the accelerometer and dynamic pressure sensors, and 8 kHz for the hydrophone. This is the first publicly available dataset for advancing leak detection and localization research, model validation, and generating new data for faulty sensor detection in water distribution systems.

Pan-HSP90 ligand binding reveals isoform-specific differences in plasticity and water networks.

Isoforms of heat shock protein 90 (HSP90) fold oncoproteins that facilitate all 10 hallmarks of cancer. However, its promise as a therapeutic target remains unfulfilled as there is still no FDA-approved drug targeting HSP90 in disease. Among the reasons hindering progress are side effects caused by pan-HSP90 inhibition. Selective targeting of the four isoforms is challenging due to high sequence and structural similarity. Surprisingly, while decades of drug discovery efforts have produced almost 400 human HSP90 structures, no single ligand has been structurally characterized across all four human isoforms to date, which could reveal structural differences to achieve selectivity. To better understand the HSP90 landscape relevant for ligand binding and design we take a three-pronged approach. First, we solved the first complete set of structures of a single ligand bound to all four human isoforms. This enabled a systematic comparison of how side-chains and water networks respond to ligand binding across isoforms. Second, we expanded our analysis to publicly available, incomplete isoform-ligand series with distinct ligand chemistry. This highlighted general trends of protein and water mobility that differ among isoforms and impact ligand binding. Third, we further probed the Hsp90α conformational landscape for accommodating a congeneric series containing the purine scaffold common to HSP90 inhibitors. This revealed how minor ligand modifications flip ligand poses and perturb water and protein conformations. Taken together, this work illustrates how a systematic approach can shed new light on an "old" target and reveal hidden isoform-specific accommodations of congeneric ligands that may be exploited in ligand discovery and design.

Allosteric Molecular Switches in Metabotropic Glutamate Receptors.

Metabotropic glutamate receptors (mGlu) are class C G protein-coupled receptors of eight subtypes that are omnipresently expressed in the central nervous system. mGlus have relevance in several psychiatric and neurological disorders, therefore they raise considerable interest as drug targets. Allosteric modulators of mGlus offer advantages over orthosteric ligands owing to their increased potential to achieve subtype selectivity, and this has prompted discovery programs that have produced a large number of reported allosteric mGlu ligands. However, the optimization of allosteric ligands into drug candidates has proved to be challenging owing to induced-fit effects, flat or steep structure-activity relationships and unexpected changes in theirpharmacology. Subtle structural changes identified as molecular switches might modulate the functional activity of allosteric ligands. Here we review these switches discovered in the metabotropic glutamate receptor family..

Management of Microbiological Contamination of the Water Network of a Newly Built Hospital Pavilion.

The good installation, as well as commissioning plan, of a water network is a crucial step in reducing the risk of waterborne diseases. The aim of this study was to monitor the microbiological quality of water from a newly built pavilion before it commenced operation. Overall, 91 water samples were tested for coliforms, Escherichia coli, enterococci, Pseudomonas aeruginosa and Legionella at three different times: T0 (without any water treatment), T1 (after treatment with hydrogen peroxide and silver ions at initial concentration of 20 mg/L and after flushing of water for 20 min/day for seven successive days) and T2 (15 days later). Coliforms were detected in 47.3% of samples at T0, 36.3% at T1 and 4.4% at T2. E. coli was isolated in 4.4% of the samples only at T1, while enterococci appeared in 12.1% of the samples at T1 and in 2.2% at T2. P. aeruginosa was isolated in 50.5% of the samples at T0, 29.7% at T1 and 1.1% at T2. Legionella pneumophila serogroup 8 was isolated in 80.2% of the samples at T0, 36.3% at T1 and 2.2% at T2. Our results confirmed the need for a water safety plan in new hospital pavilions to prevent the risk of waterborne diseases.

Targeting the Water Network in Cyclin G-Associated Kinase (GAK) with 4-Anilino-quin(az)oline Inhibitors.

Water networks within kinase inhibitor design and more widely within drug discovery are generally poorly understood. The successful targeting of these networks prospectively has great promise for all facets of inhibitor design, including potency and selectivity for the target. Herein, we describe the design and testing of a targeted library of 4-anilinoquin(az)olines for use as inhibitors of cyclin G-associated kinase (GAK). GAK cellular target engagement assays, ATP binding-site modelling and extensive water mapping provide a clear route to access potent inhibitors for GAK and beyond.

Safety and Effectiveness of Monochloramine Treatment for Disinfecting Hospital Water Networks.

The formation of potentially carcinogenic N-nitrosamines, associated with monochloramine, requires further research due to the growing interest in using this biocide for the secondary disinfection of water in public and private buildings. The aim of our study was to evaluate the possible formation of N-nitrosamines and other toxic disinfection by-products (DBPs) in hospital hot water networks treated with monochloramine. The effectiveness of this biocide in controlling Legionella spp. contamination was also verified. For this purpose, four different monochloramine-treated networks, in terms of the duration of treatment and method of biocide injection, were investigated. Untreated hot water, municipal cold water and, limited to N-nitrosamines analysis, hot water treated with chlorine dioxide were analyzed for comparison. Legionella spp. contamination was successfully controlled without any formation of N-nitrosamines. No nitrification or formation of the regulated DBPs, such as chlorites and trihalomethanes, occurred in monochloramine-treated water networks. However, a stable formulation of hypochlorite, its frequent replacement with a fresh product, and the routine monitoring of free ammonia are recommended to ensure a proper disinfection. Our study confirms that monochloramine may be proposed as an effective and safe strategy for the continuous disinfection of building plumbing systems, preventing vulnerable individuals from being exposed to legionellae and dangerous DBPs.

Clogging process and related pressure drops in wire-wound filters: laboratory evidence.

The present work is aimed at analyzing the performance of the commercial filters used for the mechanical filtration of suspended solid particles. In particular, it is intended to evaluate the head losses due to the presence of the filter in the plant and how these losses vary depending on the circulating flow rate, the nominal porosity of the filter, and its clogging degree. Filters with interstices of different sizes, from 1 to 50 µm, were compared for the performance analysis. The polypropylene wire, in facts, wrapped around a windowed cylinder of the same material, allows the creation of meshes with the desired degree of compactness. The experiments were carried out at the Laboratory of Environmental and Maritime Hydraulics (LIDAM) in a hydraulic circuit reproducing a domestic piping system, where different water demand scenarios were analyzed. The clogging of the cartridge was made with the aid of sand particles, attached, with the help of a natural glue, to the external surface of the filter. More than 200 measurements were carried out, which showed a clear increasing trend of the head losses at the filter as the clogging degree and the circulating flow rate increase. In all cases, the trend of the pressure drop at the filter has a more than linear trend. Also, it was observed that head losses did not exhibit a marked dependence on the nominal porosity. Best performances in terms of minor head losses were obtained by the 50-µm filter.

A new topological descriptor for water network structure.

Bulk water molecular dynamics simulations based on a series of atomistic water potentials (TIP3P, TIP4P/Ew, SPC/E and OPC) are compared using new techniques from the field of topological data analysis. The topological invariants (the different degrees of homology) derived from each simulation frame are used to create a series of persistence diagrams from the atomic positions. These are averaged over the simulation time using the persistence image formalism, before being normalised by their total magnitude (the L1 norm) to ensure a size independent descriptor (L1NPI). We demonstrate that the L1NPI formalism is suitable for the analysis of systems where the number of molecules varies by at least a factor of 10. Using standard machine learning techniques, a basic linear SVM, it is shown that differences in water models are able to be isolated to different degrees of homology. In particular, whereas first degree homology is able to distinguish between all atomistic potentials studied, OPC is the only potential that differs in its second degree homology. The L1 normalised persistence images are then used in the comparison of a series of Stillinger-Weber potential simulations to the atomistic potentials and the effects of changing the strength of three-body interactions on the structures is easily evident in L1NPI space, with a reduction in variance of structures as interaction strength increases being the most obvious result. Furthermore, there is a clear tracking in L1NPI space of the λ parameter. The L1NPI formalism presents a useful new technique for the analysis of water and other materials. It is approximately size-independent, and has been shown to contain information as to real structures in the system. We finally present a perspective on the use of L1NPIs and other persistent homology techniques as a descriptor for water solubility.

Edge analytics for anomaly detection in water networks by an Arduino101-LoRa based WSN.

This paper presents a novel distributed data analytic architecture, and corresponding algorithms that apply to infrastructure anomaly detection. The proposed method mainly focuses on smart water networks, demonstrating that the highest possible sensor rate analytic performs at on-edge nodes without requiring the whole date to send back to the server. This approach saves communication costs and lengthens the lifetime of the battery-powered nodes. A complex set of tasks is developed on a single-core Intel Curie processor, Arduino101 and the raw sensor data is compressed using a customized Lempel-Ziv compression algorithm tailored to resource-constrained embedded systems. The compression rate figures are then analyzed but only the compressed data which is associated with the anomalous condition is sent back to the server by means of a LoRa platform. The developed system is evaluated experimentally and the results verify the high resource utilization.

Insights into the effect of molecular crowding on the structure, interactions and functions of siRNA-PAZ complex through molecular dynamics studies.

siRNA molecules are well known to be involved in the post-transcriptional regulation of gene expression and play a key role in understanding the intricacies of eukaryotic gene regulation. While it is widely known that 3' end of siRNA binds to the PAZ domain of Argonaute proteins, it remains unclear whether the molecular crowding facilitates or hinders the overall siRNA-protein interactions during RNA interference. The biological interaction networks controlling the cellular functions of any biological cell may behave very differently in crowded environment as compared to the dilute conditions. Therefore, it is of interest to study the siRNA-protein interactions under more physiologically relevant conditions. In our previous work, we studied the role of hydrogen bond interactions and water network interactions towards the structural integrity of siRNA-PAZ complex. We also described the motions relevant for the functioning of the complex and analyzed the biphasic interaction of the 3' end of siRNA within the PAZ domain under aqueous condition. In the present work, we studied the dynamics of siRNA-PAZ complex in the presence of water-soluble crowding agent. We observed significant changes in interactions and dynamics of siRNA-PAZ complex in the presence of crowder. The conserved H-bond interactions were destabilized by ≈12%, while interfacial water networks were stabilized in the presence of crowder. The analysis of siRNA-PAZ dynamics revealed the stabilizing role of ARG52, ARG172, LYS53 and LYS173 in siRNA-PAZ complex. Interestingly, despite increase in flexibility as measured by RMSD, crowding stabilized top modes. Communicated by Ramaswamy H. Sarma.

The Molecular Origin of Enthalpy/Entropy Compensation in Biomolecular Recognition.

Biomolecular recognition can be stubborn; changes in the structures of associating molecules, or the environments in which they associate, often yield compensating changes in enthalpies and entropies of binding and no net change in affinities. This phenomenon-termed enthalpy/entropy (H/S) compensation-hinders efforts in biomolecular design, and its incidence-often a surprise to experimentalists-makes interactions between biomolecules difficult to predict. Although characterizing H/S compensation requires experimental care, it is unquestionably a real phenomenon that has, from an engineering perspective, useful physical origins. Studying H/S compensation can help illuminate the still-murky roles of water and dynamics in biomolecular recognition and self-assembly. This review summarizes known sources of H/ S compensation (real and perceived) and lays out a conceptual framework for understanding and dissecting-and, perhaps, avoiding or exploiting-this phenomenon in biophysical systems.

Up to what point is loss reduction environmentally friendly?: The LCA of loss reduction scenarios in drinking water networks.

In a context of increasing water shortage all over the world, water utilities must minimise losses in their distribution networks and draw up water loss reduction action plans. While leak reduction is clearly an important part of sustainable water management, its impacts have to be reconsidered in a broader objective of environmental protection than strictly the avoided losses in cubic metres of water. Reducing the volume of water abstracted reduces also environmental impacts associated to water production (the operation and infrastructure needed for abstraction, treatment, supply). In the mean time, activities for reducing water losses generate their own environmental impacts, notably as a result of the work, equipment, and infrastructures used for this purpose. In this study, Life Cycle Assessment (LCA) was used to assess and compare two sets of environmental impacts: those resulting from the production and supply of water which will never reach subscribers, and those caused by water loss reduction activities. This information can then be used to establish whether or not there is a point beyond which loss reduction is no longer effective in reducing the environmental impacts of drinking water supply. Results show that the improvement actions that start from a low water supply efficiency are clearly beneficial for ecosystems, human health and preservation of resources. When seeking to improve the efficiency beyond certain values (about 65%), the uncertainty makes it impossible to conclude for an environmental benefit on all impact categories.