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Structure-based virtual screening plays an important role in drug discovery and complements other screening approaches. In general, protein crystal structures are prepared prior to docking in order to add hydrogen atoms, optimize hydrogen bonds, remove atomic clashes, and perform other operations that are not part of the x-ray crystal structure refinement process. In addition, ligands must be prepared to create 3-dimensional geometries, assign proper bond orders, and generate accessible tautomer and ionization states prior to virtual screening. While the prerequisite for proper system preparation is generally accepted in the field, an extensive study of the preparation steps and their effect on virtual screening enrichments has not been performed. In this work, we systematically explore each of the steps involved in preparing a system for virtual screening. We first explore a large number of parameters using the Glide validation set of 36 crystal structures and 1,000 decoys. We then apply a subset of protocols to the DUD database. We show that database enrichment is improved with proper preparation and that neglecting certain steps of the preparation process produces a systematic degradation in enrichments, which can be large for some targets. We provide examples illustrating the structural changes introduced by the preparation that impact database enrichment. While the work presented here was performed with the Protein Preparation Wizard and Glide, the insights and guidance are expected to be generalizable to structure-based virtual screening with other docking methods.

Generating the appropriate protonation states of drug-like molecules in solution is important for success in both ligand- and structure-based virtual screening. Screening collections of millions of compounds requires a method for determining tautomers and their energies that is sufficiently rapid, accurate, and comprehensive. To maximise enrichment, the lowest energy tautomers must be determined from heterogeneous input, without over-enumerating unfavourable states. While computationally expensive, the density functional theory (DFT) method M06-2X/aug-cc-pVTZ(-f) [PB-SCRF] provides accurate energies for enumerated model tautomeric systems. The empirical Hammett–Taft methodology can very rapidly extrapolate substituent effects from model systems to drug-like molecules via the relationship between pK T and pK a . Combining the two complementary approaches transforms the tautomer problem from a scientific challenge to one of engineering scale-up, and avoids issues that arise due to the very limited number of measured pK T values, especially for the complicated heterocycles often favoured by medicinal chemists for their novelty and versatility. Several hundreds of pre-calculated tautomer energies and substituent pK a effects are tabulated in databases for use in structural adjustment by the program Epik , which treats tautomers as a subset of the larger problem of the protonation states in aqueous ensembles and their energy penalties. Accuracy and coverage is continually improved and expanded by parameterizing new systems of interest using DFT and experimental data. Recommendations are made for how to best incorporate tautomers in molecular design and virtual screening workflows.

Resting‐state functional magnetic resonance imaging (fMRI) has been used in numerous studies to map networks in the brain that employ spatially disparate regions. However, attempts to map networks with high spatial resolution have been hampered by conflicting technical demands and associated problems. Results from recent fMRI studies have shown that spatial resolution remains around 0.7 × 0.7 × 0.7 mm3, with only partial brain coverage. Therefore, this work aims to present a novel fMRI technique that was developed based on echo‐planar‐imaging with keyhole (EPIK) combined with repetition‐time‐external (TR‐external) EPI phase correction. Each technique has been previously shown to be effective in enhancing the spatial resolution of fMRI, and in this work, the combination of the two techniques into TR‐external EPIK provided a nominal spatial resolution of 0.51 × 0.51 × 1.00 mm3 (0.26 mm3 voxel) with whole‐cerebrum coverage. Here, the feasibility of using half‐millimetre in‐plane TR‐external EPIK for resting‐state fMRI was validated using 13 healthy subjects and the corresponding reproducible mapping of resting‐state networks was demonstrated. Furthermore, TR‐external EPIK enabled the identification of various resting‐state networks distributed throughout the brain from a single fMRI session, with mapping fidelity onto the grey matter at 7T. The high‐resolution functional image further revealed mesoscale anatomical structures, such as small cerebral vessels and the internal granular layer of the cortex within the postcentral gyrus. TR‐external EPIK enabled the identification of various resting‐state networks distributed throughout the brain from a single fMRI session, with mapping fidelity onto the grey matter at 7T. Network‐specific probability profiles additionally showed signal variation within the cortical regions. Our high‐resolution functional image further revealed mesoscale anatomical structures, such as small cerebral vessels and the internal granular layer of the cortex within the postcentral gyrus.

Karst aquifers are highly vulnerable to contamination due to their unique hydrogeological characteristics and increasing anthropogenic pressures. Given the challenges and costs associated with remediation, this study evaluates the groundwater vulnerability of karst formations in the Western Amazon Basin using three assessment methods: EPIK, DRASTIC, and DRASTIC-LUC. Geospatial data and sensitivity analysis were employed to assess the Napo Karst Formation. The results show that DRASTIC and EPIK classified 45.76% and 35.38% of the area as highly vulnerable, while DRASTIC-LUC classified 57.47% as moderately vulnerable. Sensitivity analysis identified depth to the water table and infiltration conditions as the most critical factors influencing vulnerability. The moderate-to-high vulnerability observed raises concerns about the risks to both surface and groundwater resources, which local populations heavily depend on. This study provides a valuable baseline for future research and offers essential guidance for decision-makers to mitigate activities that could degrade water quality in the Western Amazon Basin.

Recent laminar-fMRI studies have substantially improved understanding of the cortical responses in multiple sub-systems; in contrast, the laminar component of spread over the whole brain has been less studied due to technical limitations. Animal research strongly suggests that the supragranular layers of the cortex play a critical role in maintaining communication within the default mode network (DMN); however, whether this is true in this and other human cortical networks remains unclear. Here, we used EPIK, which offers unprecedented coverage at sub-millimeter resolution, to investigate cortical broad resting-state dynamics with depth specificity in healthy volunteers. Our results suggest that human DMN connectivity is primarily supported by intermediate and superficial layers of the cortex, and furthermore, the preferred cortical depth used for communication can vary from one network to another. In addition, the laminar connectivity profile of some networks showed a tendency to change upon engagement in a motor task. In line with these connectivity changes, we observed that the amplitude of the low-frequency-fluctuations (ALFF), as well as the regional homogeneity (ReHo), exhibited a different laminar slope when subjects were either performing a task or were in a resting state (less variation among laminae, i.e., lower slope, during task performance compared to rest). The identification of varied laminar profiles concerning network connectivity, ALFF, and ReHo, observed across two brain states (task vs. rest) has major implications for the characterization of network-related diseases and suggests the potential diagnostic value of laminar fMRI in psychiatric disorders, e.g., to differentiate the cortical dynamics associated with disease stages linked, or not linked, to behavioral changes. The evaluation of laminar-fMRI across the brain encompasses computational challenges; nonetheless, it enables the investigation of a new dimension of the human neocortex, which may be key to understanding neurological disorders from a novel perspective.

Advanced perfusion‐weighted imaging (PWI) methods that combine gradient echo (GE) and spin echo (SE) data are important tools for the study of brain tumours. In PWI, single‐shot, EPI‐based methods have been widely used due to their relatively high imaging speed. However, when used with increasing spatial resolution, single‐shot EPI methods often show limitations in whole‐brain coverage for multi‐contrast applications. To overcome this limitation, this work employs a new version of EPI with keyhole (EPIK) to provide five echoes: two with GEs, two with mixed GESE and one with SE; the sequence is termed “GESE‐EPIK.” The performance of GESE‐EPIK is evaluated against its nearest relative, EPI, in terms of the temporal signal‐to‐noise ratio (tSNR). Here, data from brain tumour patients were acquired using a hybrid 3T MR‐BrainPET scanner. GESE‐EPIK resulted in reduced susceptibility artefacts, shorter TEs for the five echoes and increased brain coverage when compared to EPI. Moreover, compared to EPI, EPIK achieved a comparable tSNR for the first and second echoes and significantly higher tSNR for other echoes. A new method to obtain multi‐echo GE and SE data with shorter TEs and increased brain coverage is demonstrated. As proposed here, the workflow can be shortened and the integration of multimodal clinical MR‐PET studies can be facilitated.

Earthquakes are among the most catastrophic natural disasters, primarily due to their immediate potential to cause loss of human life. However, their impact extends beyond the initial seismic event, particularly in karst systems, where groundwater resources are highly sensitive to geodynamic disturbances. The abundance of karst springs within these terrains makes them critical water sources for many communities, yet earthquakes can significantly disrupt their discharge patterns and degrade water quality. This study examines the vulnerability of karst springs to seismic activity, focusing on two case studies that illustrate distinct earthquake-induced hydrogeological effects. The first case investigates the temporary failure of the Opačac Spring near Imotski, Croatia, following the Mw 3.7 earthquake on 7 September 2018. This spring experienced a complete cessation of discharge for four days, as recorded by continuous hydrograph monitoring, before recovering due to the release of accumulated groundwater behind a temporarily blocked conduit. The second case explores the impact of seismic activity on water quality, focusing on the sensitive freshwater lens of the karstic Island of Vis in response to the Mw 6.1 earthquake on 22 April 2022, near Stolac, Bosnia and Herzegovina. Despite the epicenter being over 150 km away, water quality monitoring revealed notable changes, emphasizing the influence of seismic disturbances on fragile groundwater systems in carbonate island environments. Using a multidisciplinary approach, integrating seismic data analysis with hydrological and hydrogeological observations, this study investigates the mechanisms through which earthquakes alter karst water systems. A proposed vulnerability assessment framework is introduced, aiming to correlate earthquake intensity, proximity, and hydrogeological response to better predict karst spring failure and water quality degradation. This model provides valuable insights for disaster preparedness, water resource management, and risk mitigation strategies in karst terrains, highlighting the necessity of incorporating karst hydrogeology into regional earthquake response planning.

Seawater intrusion has become a growing threat in coastal urban cities due to overexploitation of groundwater. This study examines the accuracy of the commonly used geospatial quality assessment models (GQA) and groundwater vulnerability assessment models (GVA) in determining the extent of seawater intrusion in urban coastal aquifers. For that purpose, interpolation methods (kriging, IDW and co-kriging) and vulnerability assessment models (DRASTIC, EPIK) were compared using groundwater salinity criteria (TDS, Cl−) collected at three pilot areas along the eastern Mediterranean (Beirut, Tripoli, Jal el Dib). The results showed that while the GIS-based interpolation methods and the vulnerability assessment models captured elements of the groundwater quality deterioration, both had a limited ability to accurately delineate saltwater intrusion. This emphasizes that while interpolation methods and conventional vulnerability models may give general information about groundwater quality, they fail to capture the status of the aquifer at a finer spatial resolution.

This is a full-scale edition with commentary of the archaic epic poems Oichalias Halosis by Kreophylos of Samos and Herakleia by Peisandros of Kamiros. The Greek text (divided between testimonies and fragments) is accompanied by detailed critical apparatus and English translation. There are also extensive introductions to the biography of each poet, the title of the poem, its content and style, as well as a careful examination of the relative chronology of each epic. The detailed commentary of every fragment offers an up-to-date examination of all the extant material that has come down to us through a rich indirect tradition. This is the second installment of the project Early Greek Epic Poets (vol. I: Genealogical and Antiquarian Epic, De Gruyter 2017), which aims to enhance the study of Greek epic poetry of the archaic and classical period by means of providing readers with authoritative editions and commentaries of a significant part of fragmentary early Greek epic.

Who speaks? The author as producer, the contingency of the text, intertextuality, the \"device\"-core ideas of modern literary theory-were all pioneered in the shadow of oral literature. Authorless, loosely dated, and variable, oral texts have always posed a challenge to critical interpretation. When it began to be thought that culturally significant texts-starting with Homer and the Bible-had emerged from an oral tradition, assumptions on how to read these texts were greatly perturbed. Through readings that range from ancient Greece, Rome, and China to the Cold War imaginary, The Ethnography of Rhythm situates the study of oral traditions in the contentious space of nineteenth- and twentieth-century thinking about language, mind, and culture. It also demonstrates the role of technologies in framing this category of poetic creation. By making possible a new understanding of Maussian \"techniques of the body\" as belonging to the domain of Derridean \"arche-writing,\" Haun Saussy shows how oral tradition is a means of inscription in its own right, rather than an antecedent made obsolete by the written word or other media and data-storage devices.